Next Article in Journal
Activation of Mammary Epithelial and Stromal Fibroblasts upon Exposure to Escherichia coli Metabolites
Previous Article in Journal
Metabolic Reprogramming Induced by Aging Modifies the Tumor Microenvironment
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 13
Issue 20
10.3390/cells13201722
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

PKD2: An Important Membrane Protein in Organ Development

by
Shuo Wang
1,2,†,
Yunsi Kang
1,2,† and
Haibo Xie
1,2,*
1
MoE Key Laboratory of Evolution and Marine Biodiversity, Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao 266003, China
2
College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2024, 13(20), 1722; https://doi.org/10.3390/cells13201722
Submission received: 25 August 2024 / Revised: 11 October 2024 / Accepted: 16 October 2024 / Published: 17 October 2024
Browse Figures
Versions Notes

Abstract

:
PKD2 was first identified as the pathogenic protein for autosomal dominant polycystic kidney disease (ADPKD) and is widely recognized as an ion channel. Subsequent studies have shown that PKD2 is widely expressed in various animal tissues and plays a crucial role in tissue and organ development. Additionally, PKD2 is conserved from single-celled organisms to vertebrates. Here, we provide an overview of recent advances in the function of PKD2 in key model animals, focusing on the establishment of left–right organ asymmetry, renal homeostasis, cardiovascular development, and signal transduction in reproduction and mating. We specifically focus on the roles of PKD2 in development and highlight future prospects for PKD2 research.

1. Introduction

PKD2 was identified by Mochizuki in 1996 from three family lineages of autosomal dominant polycystic kidney disease (ADPKD) patients [1]. Currently, approximately 1 in 400 to 1 in 1000 newborns are affected by ADPKD [2]. Mutations in PKD2 are estimated to account for approximately 15% of ADPKD cases [3]. In contrast, PKD1 mutations, responsible for around 85% of ADPKD cases, are associated with more severe disease outcomes, including larger kidney size, earlier onset of end-stage renal disease (ESRD), and more frequent complications like hypertension [4]. Despite this, PKD2 remains critical for understanding ADPKD due to its role in both renal and extrarenal tissues. PKD2 is expressed in the renal tubules of both human fetuses and adults, as well as in the epithelial of the liver, lung, bowel, brain, reproductive organs, and other tissues [5]. Additionally, PKD2 expression has also been observed in non-epithelial tissues, including vascular smooth muscle, skeletal muscle, myocardial cells, and neurons [5]. ADPKD is a multisystem disorder with lesions in other organs [6]. The interaction between the PKD1 and PKD2 gene products, polycystin-1 and polycys-tin-2, forms a complex involved in calcium signaling, which is crucial for tubular structure maintenance and cyst development. Therefore, elucidating the molecular mechanisms of organ development regulated by PKD2 is essential for the diagnosis and treatment of ADPKD.
Recent research has shown that PKD2 is a member of the TRP (transient receptor potential) ion channel family [7]. PKD2 contains six transmembrane domains: the first four TMHs (transmembrane helices) form a voltage-sensor-like domain, followed by a pore domain with two additional TMHs separated by a pore helix, a selectivity filter, and a second short pore helix [8]. The C-terminus of PKD2 contains EF-hand motifs that bind calcium ions, as well as a coiled-coil domain [9,10]. Cryo-electron microscopy shows that PKD2 assembles into homotetramers [8,11,12] and can also form heterotetramers with PKD1 [13]. PKD2 is typically localized in the endoplasmic reticulum (ER) and cilia. PKD2 forms non-selective calcium ion or voltage-activated cation channels in the ER [14,15]. Ciliary PKD2 is a non-selective cation channel protein involved in the transduction of mechanical signals [16,17,18,19,20]. While significant progress has been made in understanding the cellular localization and structure of PKD2, more attention is now being paid to elucidating its physiological functions in complex organisms.
PKD2 is conserved in most animals (Figure 1A) [21,22,23,24,25,26,27,28,29,30,31]. Recent research shows diverse functions of PKD2 in various organisms, especially in multicellular ones [32,33,34,35,36,37,38,39]. Therefore, elucidating the diverse physiological functions of PKD2 using various model organisms, characterizing its functional properties in specific organs, and deciphering the common mechanisms underlying developmental abnormalities caused by PKD2 dysfunction are focal points in developmental biology. Here, we highlight the research progress on PKD2 in model species from the perspective of organ development (Figure 1B) and discuss future research directions for understanding PKD2’s physiological functions.

2. PKD2 and Left–Right Asymmetry

Internal organs are asymmetrically distributed in most vertebrates. In humans, incorrect left–right asymmetry of internal organs is often associated with disorders, such as congenital heart disease [40,41]. PKD2 plays an essential role in establishing left–right asymmetry during the embryonic development of vertebrates [42]. PKD2 dysfunction results in defective left–right patterning in humans, mice, zebrafish, and frogs [32,33,34,35].
The left–right organizer (LRO) is a key tissue for left–right patterning, including the node in humans and mice [33], Kupffer’s vesicle in zebrafish [34], and the gastrocoel roof plate in frogs [43,44]. Primary and motile cilia are abundant in the LRO, where the coordinated beating of motile cilia generates fluid flow towards the left side, allowing immotile cilia to sense the mechanical signals from the leftward flow and initiate the first asymmetric event in embryonic development [45,46,47]. Mechanical force causes the primary cilia on the left side of the LRO to bend towards the ventral side and the primary cilia on the right side to bend towards the dorsal side, resulting in greater tension on the dorsal side of the left cilia, which activates PKD2 enriched on the dorsal side and induces changes in calcium signaling in both the cilia and cytoplasm of the left-side cells of the LRO (Figure 2A) [19,20,46]. In zebrafish, the stronger bending of immotile cilia on the left side of the KV is the reason for the calcium signals in the left-side cells of the LRO [19]. Defects in the motility of cilia in the LRO lead to abnormal left–right asymmetry in organ development [44]. Left–right asymmetry defects in zebrafish c21orf59 (motile cilia gene) morphants can be counteracted by using optical tweezers to manipulate the primary cilia on the left side of Kupffer’s vesicle, but this method cannot rescue the left–right asymmetry defects in zebrafish pkd2 morphants [19]. Consistent with zebrafish, mechanical stimuli administered to primary cilia by optical tweezers also trigger signals for the establishment of left–right patterning in mice [19]. These data confirm that PKD2 acts as a mechanosensor on the ciliary membrane to regulate calcium signaling in the left-side cells of LRO, directly promoting the establishment of left–right asymmetry of internal organs [19,20].
Activation of calcium signaling mediated by PKD2 in left-side cells of the LRO leads to Bicc1 interacting with Ccr4 to form a degradation complex for Dand5 mRNA, ultimately inhibiting Dand5 expression in the left-sided lateral plate mesoderm [48,49,50]. Degradation of Dand5 activates Nodal signaling in the left lateral plate mesoderm and enhanced Nodal signaling activates the expression of Lefty2 and Pitx2 in the left lateral plate mesoderm (Figure 2B) [49,51,52,53,54,55,56,57,58]. These events collectively determine the establishment of left–right asymmetry in internal organs [59].

3. PKD2 and Kidney

PKD2 plays a crucial role in maintaining the structure and function of the kidney. Mutations in PKD2 can lead to autosomal dominant polycystic kidney disease (ADPKD), a multisystem and progressive adult-onset genetic disorder characterized by the formation of fluid-filled cysts and increased kidney volume [60]. The “two-hit” model has been proposed to explain the genetic mechanism of renal cyst formation caused by PKD2 mutations [61,62]: (1) Both proximal and distal tubular epithelial cells of all nephrons carry both mutant and non-mutant PKD2 alleles, which means the individual has a heterozygous germline mutation, which represents the first hit; (2) injuries or other factors may cause mutations in the non-mutant PKD2 allele, resulting in somatic mutations, which represents the second hit, leading to insufficient PKD2 levels in the cells.

3.1. Function of PKD2 in Mouse Kidney

Both mouse and human kidneys belong to the metanephros, indicating that they share a structure that is highly similar in nature [63,64]. Pkd2 mRNA expression is detectable in the cortical region of adult mouse kidneys [65,66]. PKD2 is also expressed in the loop of Henle and distal convoluted tubules of mouse kidneys, where it localizes to the basal lateral membrane and cilia of epithelial cells [67,68]. Homozygous mutants of mouse Pkd2 die at embryonic day 13.5, exhibiting defects in the atrioventricular septum, renal cysts, and pancreatic cysts, while heterozygotes show milder pancreatic cysts, suggesting a dosage-dependent regulation of tissue function in mouse kidneys by PKD2 [69].

3.1.1. PKD2 Regulates Intracellular Calcium Homeostasis in Renal Cells

In mouse kidneys, PKD2 on cilia responds to mechanical signals from extracellular fluid flow, triggering changes in intracellular calcium signaling. Ryanodine receptors are located on the endoplasmic reticulum and are involved in the release of calcium ions from intracellular calcium stores into the cytoplasm [70]. Ryanodine receptor inhibitors can block this signal transduction, highlighting the significance of Ryanodine receptors in this process [68]. PKD2 in the ER interacts with the N-terminus of inositol 1,4,5-trisphosphate receptor (IP3R) via its C-terminus, a process activated by low calcium that leads to the release of higher calcium from the ER [71]. PKD2 shows higher permeability to potassium ions than to calcium ions. Overexpression of the trimeric intracellular cation channel TRIC-B (potassium channel) corrects defects in ER calcium ion release and inhibits cyst formation, whereas TRIC-B deficiency exacerbates cyst formation in Pkd2 heterozygous kidneys, which suggests that PKD2 in the ER may function as a potassium ion channel, facilitating potassium–calcium ion exchange and thereby regulating intracellular calcium ion concentrations through IP3R-mediated mechanisms [72]. PKD2 is localized to the cell membrane of mouse inner medullary collecting duct cells and Madin–Darby canine kidney cells, functioning as an ion channel, which suggests that external signals can be transduced by PKD2 on the cell membrane [73]. Post-translational modifications of PKD2, specifically phosphorylation of Ser812 by Casein Kinase II, play a role in regulating how PKD2 functions as an ion channel [74]. Single-channel studies show that both PKD2 and its S812A variant function as divalent cation channels with comparable current amplitudes under various holding potentials, exhibiting open probabilities dependent on cytoplasmic calcium ions in a bell-shaped manner; however, S812A shows significantly reduced sensitivity to calcium ion activation/inactivation, being 10-fold less sensitive than the wild-type PKD2 channel [74].

3.1.2. PKD2 Regulates Cell Proliferation in Mouse Kidney

Over-proliferation of renal tubular epithelial cells occurs in both heterozygous and homozygous Pkd2 mutant mice before cyst formation [75]. Furthermore, reports indicate that PKD2 is overexpressed in human renal cyst tissues and can induce renal cysts in mice when overexpressed under model human PKD2 conditions [5,76]. The causes of polycystic kidney disease due to PKD2 mutation can currently be categorized into three main aspects (Figure 3A,B).

3.1.3. PKD2 Regulates Cell Proliferation through Calcium Signaling

In the cystic epithelial cells of Pkd2 mutant mouse kidneys, decreased intracellular calcium ions reduce the calcium-mediated inhibition of adenylyl cyclase 5/6 (a plasma membrane-bound enzyme with multiple calcium-sensitive subtypes), thereby increasing cellular cAMP levels [77,78,79,80]. Elevated cAMP levels in the cholangiocytes resulting from PKD2 deficiency enhance protein kinase A (PKA) activity, which leads to ERK phosphorylation (pERK), stimulating VEGF signaling, which ultimately activates cell proliferation and promotes the formation of hepatic cysts [81]. In the kidneys, activated PKA can phosphorylate cAMP responsive element-binding protein (CREB), driving the transcription of target genes in pathways related to cell proliferation [82]. Recent studies show that PKA phosphorylates serine158 of HEXIM1, which inactivates the P-TEFb/HEXIM1/7SK snRNP complex, releasing and activating the central transcriptional elongation regulator (positive transcription elongation factor b, P-TEFb), thereby promoting cell proliferation [83]. Moreover, P-TEFb is overexpressed in mouse and human renal cysts, and the activation of P-TEFb facilitates the establishment of the zebrafish renal cyst model [83]. Overexpression of human PKD2 in mice results in mitotic instability and centrosome overduplication of renal cells and promotes cell proliferation, which may be linked to excessive activation of the B-Raf/MEK/ERK phosphorylation by PKA (Figure 3B) [84,85].

3.1.4. PKD2 Interacts with Transcription Factors to Regulate Cell Proliferation

Phosphorylated PKD2 (S812) interacting with the inhibitor of DNA Binding 2 (ID2) sequesters the ID2-E47 complex in the cytoplasm and prevents ID2 from inhibiting p21 activation, which reduces cyclin-dependent kinase 2 (CDK2) activity and inhibits cell proliferation [86,87]. Enhanced nuclear localization of ID2 has been observed in human and mouse renal cysts, suggesting that ID2 plays a pivotal role in PKD2-mediated cell cycle regulation [86,87]. Mutations in PKD2 result in increased nuclear ID2 levels, potentially regulating the activation of E2F transcription factors by interacting with the retinoblastoma (Rb) transcriptional corepressor, thereby enhancing cell proliferation [88]. Elevated ID2 levels may also bind basic helix–loop–helix transcription factors (bHLH) to suppress p21 gene expression, which enhances CDK2/CDK4-mediated Rb phosphorylation, resulting in the release of E2F from the Rb-E2F complex and cell proliferation (Figure 3B) [88].

3.1.5. PKD2 Regulates Cell Proliferation through Energy Metabolism

Mitofusin 2 (MFN2, an outer mitochondrial membrane GTPase facilitating mitochondria-ER proximity) expression was increased in PKD2 knockdown cell culture models and cyst-lining epithelial cells from human ADPKD kidneys, which enhances calcium transfer efficiency into mitochondria and promotes mitochondrial respiration (Figure 3B) [89]. Knockdown of MFN2 restored defective mitochondrial calcium ion transfer and reduced cell proliferation in mouse with kidney cysts, suggesting that PKD2 acts as a regulator of mitochondrial biogenesis and bioenergetics by regulating essential mitochondrial proteins at the ER–mitochondrial junction [89]. Studies on PKD1 indicate that increased proliferation of cystic renal epithelial cells elevates intracellular ATP levels, which inhibit AMP-activated protein kinase (AMPK) activity and prevents AMPK from phosphorylating tuberous sclerosis complex 2 (phosphorylated TSC2 suppresses mTORC1 kinase activity), leading to enhanced protein synthesis and cell proliferation (Figure 3B) [90,91].

3.1.6. PKD2 Maintains the Polarity of Cells

Epithelial cell polarity is crucial for maintaining the structural and functional integrity of the kidney. Pkd2 mutant mice exhibit increased expression of β-catenin, axin2, and cMyc, indicating disrupted canonical Wnt signaling [92]. Disrupted E-cadherin-mediated cell–cell contacts result in significantly elevated cytoplasmic β-catenin levels, which impede renal epithelial polarization [92].

3.1.7. PKD2 Is Involved in the Development of Cilia in Mouse Kidneys

In vitro experiments demonstrate that PKD2-mediated mechanotransduction regulates cilia length in mammalian epithelial and mesenchymal cells [93]. However, the regulation of ciliary length by PKD2 remains controversial. There are fewer and shorter cilia in renal epithelial cells of PKD2-deficient mice [92], while the cilia of PKD2-deficient cyst-lining tubule cells are longer than the control group from another report [17]. Interestingly, the study showed that cilia integrity contributes to renal cyst formation caused by PKD2 deficiency, although the mechanism of this is not clear [94]. Recent studies have shown that the loss of PKD1 in mice alters the biomechanical properties of the basement membrane of renal tubules in a cilia-dependent manner, ultimately resulting in distal renal tubule dilation and cyst formation independent of cell proliferation [95]. This discovery may suggest a potential similar regulatory role for PKD2 in cystogenesis.

3.2. Function of PKD2 in Zebrafish Kidney

Zebrafish have pronephros during the embryo stage and mesonephros during the adult stage, with nephron units segmented similarly to mammalian kidneys [63]. Pkd2 in zebrafish is located at the basal lateral membrane of the pronephric duct [96]. Zebrafish pkd2 mutants do not develop polycystic kidneys [97]. However, there are pronephric cysts in the pkd2 morphant due to pronephric duct blockage [37,96,98]. Knockdown of Pkd2 reduces levels of Scribble at the basal membrane, inhibiting the Hippo signaling pathway and causing cytoplasmic YAP to translocate to the nucleus, which promotes glomerular cyst formation [99]. The N-terminal GSK-3β phosphorylation site of Pkd2 facilitates its localization to the lateral cell membrane [100], while the C-terminal acidic cluster/PACS binding domain promotes Pkd2 retention in the ER/Golgi membrane [96,101]. Mislocalization of Pkd2 affects the structural integrity and function of zebrafish renal tissues [96,100]. However, current research suggests that Pkd2 does not directly participate in the physiological function of zebrafish kidneys through cilia development and function [96,98].

3.3. Progress in Clinical Drug Research on ADPKD

Recent advancements in understanding the pathophysiology of diseases have led to new potential therapeutic targets. PKD2 regulates cell proliferation through calcium signaling. For example, Tolvaptan, a vasopressin V2 receptor antagonist, reduces cAMP levels and is currently used to slow the progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD) [102]. Additionally, somatostatin analogs, such as Octreotide and Lanreotide, have been reported to delay the growth of renal cysts [103]. The pan-histone deacetylase (HDAC) inhibitor, trichostatin A, has also shown promise in reducing cyst progression and slowing kidney function decline [88]. Moreover, recent studies indicate that everolimus and sirolimus, both mTOR inhibitors, can slow renal cyst progression [104]. PKD2 maintains cell polarity, and while promising β-catenin inhibitors are under investigation, their approval for ADPKD remains uncertain [105].

4. PKD2 and Cardiovascular

4.1. PKD2 Regulates Cardiac Development

4.1.1. PKD2 Is Involved in the Formation of the Atrioventricular Valves

In zebrafish, early blood flow in the heart generates mechanical signals. Pkd2 of atrioventricular endocardial cells transduces mechanical signals to regulate intracellular calcium ion concentration, and then calcium ion/calmodulin-dependent protein kinase Camk2g activates the expression of klf2a to promote valve formation [38,106,107].

4.1.2. PKD2 Is Involved in Cardiac Contraction and Relaxation

In mouse cardiomyocytes, PKD2 can interact with the cardiac ryanodine receptor (RyR2) [108]. The C-terminus of PKD2 functionally inhibits RyR2 channel activity in the presence of calcium, resulting in altered calcium signaling in the heart [108]. Additionally, heterozygous PKD2 decreases calcium ion concentration in the sarcoplasmic reticulum, which leads to increased PKA-mediated phosphorylation of cardiac troponin I and decreased β-adrenergic signaling-mediated dephosphorylation of phospholamban (PLB) and ultimately altering myocardial contractility [109]. Similarly, pkd2 mutation in zebrafish dysregulates calcium ion homeostasis in cardiomyocytes, leading to abnormal cardiac contraction and relaxation [110]. PKD2 is also expressed in intestinal smooth muscles in fruit flies and PKD2 deficiency reduces food intake and waste excretion in larvae, which indicates that PKD2 regulates the contractility of smooth muscle [39]. Additionally, PKD2 regulates the contractility of tracheal smooth muscle in mice [111].

4.1.3. PKD2 Is Involved in Cardiac Protection under Stress

Under stress, mice exhibited increased left ventricular mass along with elevated levels of PKD2, chromogranin B (CGB, an upstream regulator of BNP), and natriuretic peptides (ANP and BNP) [112]. After stress cessation, the left ventricular mass returned to baseline [112]. However, PKD2-deficient mice failed to upregulate cardioprotective atrial natriuretic peptides during stress and their left ventricular mass failed to recover after stress cessation, suggesting the involvement of PKD2 in cardiac protection during emergencies [112].

4.2. PKD2 Is Involved in Vascular Development

PKD2 localizes at the sarcoplasmic reticulum and ciliary membrane in the smooth muscle cells of mouse aortas [113,114,115]. Abnormal function of PKD2 is linked to hypertension and structural vascular abnormalities, including intracranial aneurysms [116]. Hypertension associated with PKD2 deficiency can manifest in childhood and precede the onset of kidney disease [117].

4.2.1. PKD2 Is Involved in the Establishment of Vascular and Lymphatic Networks

In mice, homozygous Pkd2 mutants display severe edematous vascular phenotypes linked to lymphatic developmental defects, including reduced lymphatic vessel density, impaired vascular branching, and abnormal migration of early lymphatic endothelial cell precursors [118]. Knockdown of pkd2 in zebrafish results in abnormal development of the caudal vein [119]. Live imaging shows that endothelial cilia bend in response to blood flow in zebrafish embryos and affect intracellular calcium concentrations, which indicates that Pkd2, located in cilia, senses blood flow shear forces to regulate vascular network development [119]. Moreover, Zebrafish Pkd2 senses radial shear force and circumferential pressure from blood flow, participating in vascular morphogenesis through the regulation of endothelial cell rearrangement, shape changes, cell division orientation, and extrusion/layering [120]. Although PKD2 typically functions alongside primary cilia, suggesting that its role may depend on the presence of cilia, studies indicate that the regulation of endothelial cell area appears to be achieved through cilia-mediated flow sensing. In contrast, the regulation of endothelial cell extrusion may rely on cilia-independent mechanosensitivity mediated by PKD2 [120]. This finding reveals distinct regulatory mechanisms.

4.2.2. PKD2 Regulates Vascular Pressure by Sensing Mechanical Forces Generated by Blood Flow

Research shows that PKD2 located in the cilia of vascular endothelial cells in both mice and humans senses fluid shear stress through a complex biochemical pathway involving calcium, calmodulin, protein kinase B, and protein kinase C [115]. When exposed to fluid shear stress, mouse endothelial cells can produce nitric oxide to regulate blood pressure [115]. Studies have shown that blood flow activates PKD2 channels in endothelial cells, which causes calcium influx, potassium channel activation, phosphorylation of endothelial nitric oxide synthase, vascular hyperpolarization, dilation, and ultimately reduces blood pressure [121,122]. Intravascular pressure and α1-adrenoceptors activate PKD2 channels in arterial myocytes to regulate blood pressure by inducing an inward sodium current, membrane depolarization, and vasoconstriction [123]. Furthermore, vascular pressure and the SUMOylation dynamics of PKD2 stabilize vascular pressure by controlling PKD2 abundance on the cell membrane [124]. For example, high intravascular pressure promotes SUMO-PKD2 localization to cell membranes and low intravascular pressure results in the degradation of SUMO-PKD2 in lysosomes. Intravascular pressure activates SUMO-PKD2, not PKD2, channels, through this SUMOylation-dependent mechanism and intravascular pressure regulates the surface density of SUMO-PKD2-mediated Na+ currents (INa) in myocytes to control arterial contractility [124]. In heterozygous Pkd2 mice, mesenteric vessels exhibit impaired relaxation function, primarily due to increased vascular oxidative stress, which reduces NO bioavailability [117].

5. PKD2 and Reproduction and Mating

Defects in PKD2 function frequently result in male infertility and reproductive defects in humans [125,126]. PKD2 plays a role in the reproductive system of male mice via the TGF-β/BMP and canonical Wnt signaling pathways [127]. Disruption of PKD2 results in mesonephric tubule/efferent duct dilation, epididymal coiling failure, and defective testicular development [127]. PKD2 is also expressed in the testes of Drosophila and in all stages of sperm precursor differentiation, except for germline stem cells [128]. In mature sperm, PKD2 is found in punctate patterns at the acrosome, head, and tail [129]. Sperm with PKD2 defects have intact structures but with reduced motility [128,129,130,131,132].
In C. elegans, PKD-2 (the homolog of human PKD2) plays a role in mating behavior. PKD-2 is expressed in CEphalic Male Sensory Neuron (CEM) of the head, and Ray neuron B (Ray B), and HOok Neuron B (HOB) of the tail [133,134]. Neurons expressing PKD-2 feature an exposed cilium at the distal end of the dendrite [135]. PKD-2 localizes to the endoplasmic reticulum (ER), dendritic puncta, the cilium, and extracellular vesicles (ECVs) [133,136]. ECVs are essential for chemotaxis towards mates, response to mate contact, and locating the mate’s vulva [133,137,138,139]. ECVs containing PKD-2 are released from the tip of the nose (where CEM cilia are exposed) and male tail rays (where RnB and HOB cilia are exposed) [140]. These ECVs are directionally transferred to the hermaphrodite’s vulva during C. elegans mating [141]. ECVs containing PKD-2 induce male tail-chasing behavior, where the tail curls to contact its own head and moves in a backward circle [140]. Tail curling enables the male to contact and circle around the hermaphrodite body during mating and the release ratio of ECVs containing PKD2 increases during male mating [140,142]. Transcriptome sequencing of ECVs revealed new pathways that control ECV biogenesis, polycystin signaling, and ECV cargo [143]. For example, the proteins that participate in polycystin signaling pathways, including homologs of Tumor Necrosis Factor (TRAF), trf-1, trf-2, and the p38 MAPK pmk-1, influence male mating behaviors [143]. Deficiency and mislocalization of PKD-2 both impact mating behavior [135,136,144,145,146,147,148,149,150,151,152,153].

6. Other Diverse Functions of PKD2

6.1. Pkd2 Regulates the Development of Body Axis in Zebrafish

Loss of Pkd2 function in zebrafish results in dorsal curvature of the body axis [37]. Preliminary research indicates that Pkd2 maintains cellular calcium ion homeostasis and participates in negative feedback control of embryonic collagen gene expression via the phosphoinositide 3-kinase signaling pathway [154]. Loss of Pkd2 function upregulates Sec23A, Sec23B, Sec24C, and Sec24D, resulting in excessive accumulation of type II collagen in notochord sheath cells that may be responsible for dorsal curvature of the body axis in zebrafish [154,155]. Overexpression of Pde1a in zebrafish pkd2 morphants reduces cAMP concentration and mitigates axial curvature, which suggests that Pkd2 may influence axial morphology through the modulation of cAMP levels [156]. Drug screening shows that inhibitors of transforming growth factor receptor ALK5 kinase, diclofenac sodium, pyrithione zinc, 2,5-di-t-butyl-4-hydroxyanisole, and histone deacetylase (TSA) can inhibit tail curvature caused by Pkd2 deficiency [157,158].

6.2. PKD2 Is Involved in the Development of Skeletal System in Mice

Studies indicate that Pkd2 likely plays a crucial role in craniofacial growth. Mice with conditional deletion of Pkd2 in neural crest-derived cells exhibited signs of mechanical trauma, including fractured molar roots, distorted incisors, alveolar bone loss, compressed temporomandibular joints, and abnormal skull shapes [159]. In addition, mice with conditional deletion of Pkd2 in mature osteoblasts showed reduced bone mineral density, trabecular bone volume, cortical thickness, mineral apposition rate, and impaired biomechanical properties of bone [160]. Moreover, Pkd2 deficiency in mature osteoblasts also leads to decreased expression of peroxisome proliferator-activated receptor γ (PPARγ), reduced bone marrow fat and adipogenesis [160]. Current research suggests that PKD2 regulates the generation of the adipocytes and osteoblasts by modulating PPARγ and Runx2 [160].

6.3. Function of PKD2 in Nervous System

PKD2 in Class III (CIII) multidendritic sensory neurons of Drosophila is involved in sensing noxious cold [161]. Collar-receptor neurons in Platynereis larvae express PKD2-1 (the homolog of human PKD2) to detect environmental water flow, which may trigger a coordinated whole-body response to avoid predators [162]. In mice, PKD2 is localized to the cilia of ependymal cells, where it responds to shear force from cerebrospinal fluid [163]. The process contributes to the polarization of ependymal and choroid plexus cells by regulating the asymmetric localization of VANGL2 on the apical surface of choroid plexus cells and ciliary position [163]. Additionally, PKD2 balances proliferation and differentiation of neural progenitor cells through the Notch signaling pathway and the STAT3 transcription factor in mice [164].

7. Perspectives

ADPKD is a prevalent autosomal dominant genetic disorder, affecting 1 in 500–2500 individuals worldwide [6,165]. ADPKD is a multisystem disorder affecting the kidneys, liver, pancreas, arachnoid membrane, and heart [3,166,167,168], with 15% of patients harboring PKD2 mutations [3]. Therefore, studying PKD2 in model organisms helps elucidate its pathogenic mechanisms. Researchers have explored PKD2 functions in establishing left–right asymmetry, renal function maintenance, cardiovascular development, and signal transduction of reproductive and mating, including mice, zebrafish, C. elegans, Drosophila, and Xenopus laevis (Table 1). These studies provide crucial data for diagnosing, treating, and developing drugs for related diseases.
However, technological limitations hinder a comprehensive understanding of PKD2 function, and specific mechanisms in certain biological processes require further elucidation. The study of PKD2 using zebrafish has faced challenges due to the lack of highly specific antibodies, hindering the analysis of PKD2’s tissue distribution and subcellular localization, and limiting a comprehensive investigation of its role in organ development. Additionally, direct observation of PKD2’s polar localization in cilia in vivo could help provide insights into its role in left–right asymmetry. Although preliminary conclusions have been drawn in mice, the imaging resolution is low, and these findings have not been validated in other animal models [19,20]. Therefore, developing high-resolution imaging techniques represents a promising direction for future research. In left–right asymmetry, future research could explore how PKD2’s polarity localization in cilia is determined, the function of PKD2 in LRO centrosome polarization, and the role of calcium ions in Dand5 mRNA degradation. Left–right asymmetrical defects can lead to organ displacement and affect organ function, such as congenital heart disease [169]. PKD2 is currently thought to act as a mechanical sensor in regulating the asymmetric development of the left and right organs, and its mutation can lead to congenital heart disease [170]. Therefore, the development of related molecular drugs to treat congenital heart disease induced by PKD2 dysfunction is also an important direction in the future.
Recent studies indicate that intact cilia promote cyst formation in PKD2-mutant kidneys, challenging the current theory that PKD2 functions through cilia in the kidneys [94]. The discovery that reintroducing the TRIC-B potassium channel can rescue kidney cysts offers a new perspective for identifying drug targets to treat PKD2-induced polycystic kidney disease [72]. Some suggest that PKD1 deletion in mice alters the biomechanical properties of the renal tubular basement membrane in a cilia-dependent manner, leading to distal tubular dilation and cyst formation, independent of cell proliferation [95]. Whether PKD2 is also involved in similar physiological functions needs to be further explored.
Besides embryonic left–right asymmetry and autosomal dominant polycystic kidney disease, PKD2 is also involved in the development of other organs in model organisms. Corresponding diseases occur in humans, but underlying mechanisms are unclear. Further research is needed to understand how PKD2 contributes to cardiac development, vascular network formation, and vascular constriction. The roles of PKD2 in mammalian reproductive development, regulation of sperm motility in Drosophila, and mating of C. elegans are not fully understood. The mechanism by which loss of Pkd2 function causes body axis curvature in zebrafish also requires further investigation. One potential avenue for future research is to explore whether PKD2 influences body axis morphology either directly or indirectly by modulating neural activity and muscle contraction. Diverse subcellular localization of PKD2 contributes to its functional diversity. Therefore, employing high-resolution microscopy to study subcellular localization of PKD2 in diverse organs is crucial for understanding its function.
The current tools used to study PKD2 include the zebrafish mutant. The cup and hi4166 mutant serve as a significant model for studying PKD2 function in zebrafish [97,157]. For mouse models, the mouse mutant is used, including Pkd2nf3/nf3 and Pkd2WS25/−, which provides essential insights into the role of PKD2 in kidney development and function [171,172]. For overexpression models, the PKD2-Y transgenic mouse has been used to investigate the effects of PKD2 overexpression on kidney physiology [76]. In addition, the PKD2 mutant amo in Drosophila offers a unique perspective on PKD2 biology in invertebrate models [128]. The PKD-2 mutant in C. elegans has also been utilized to elucidate PKD2-related functions, particularly in the context of developmental processes [133]. Future priorities for the development of PKD2 animal models may include zebrafish gene knock-in. Employing zebrafish gene knock-in techniques to trace the expression patterns and subcellular localization of PKD2 could enhance our understanding of its biological roles. Utilizing conditional knockout models in both zebrafish and mice could also help determine whether PKD2 plays a critical role in kidney development and function during different life stages. Integrating these tools will not only deepen our understanding of PKD2’s functions but also advance future research in related fields.
Different animal models present distinct advantages and limitations for studying PKD2 function. (1) Mouse models offer another valuable approach, with various PKD2 knockout and transgenic strains providing insights into the gene’s role in kidney development and disease progression. These models closely mimic ADPKD [173]. However, genetic and environmental variations between species can complicate the translation of findings to clinical settings [173]. (2) Zebrafish models are particularly advantageous due to their transparency during early development and the ease of gene manipulation. This allows for real-time observation of kidney development and cyst formation. However, the physiological differences between zebrafish and mammals may limit the direct applicability of findings to human conditions [174,175]. (3) Drosophila and C. elegans models are simpler organisms that can be useful for genetic studies and high-throughput screening of potential therapeutic compounds. Nonetheless, their simplified biological systems may not fully capture the complexities associated with mammalian kidney disease [176]. In summary, while each animal model has unique strengths that can contribute to our understanding of PKD2 and its implications for human health, the limitations inherent in each model must also be carefully considered when interpreting results.
Besides model organisms, investigating the pathogenic mechanisms and functions of PKD2 using clinical samples and organoids is gaining traction. Human kidney organoids are promising for drug screening. Currently, collecting ducts cannot form in kidney organoids. Compared to in vivo conditions, kidney organoids have smaller cyst volumes and lack urine flow and vasculature [177,178,179]. Thus, improving culture conditions to better mimic in vivo environments for kidney organoids is crucial for developing treatment strategies for ADPKD in the future.
Ongoing clinical studies have significantly contributed to the understanding of PKD2 function. The studies “A Possible Founding PKD2 Mutation Associated with Variable Phenotypes of ADPKD in Bergamo Province” and “Clinical and Molecular Description of PKD1 and PKD2 Mutation Negative Carriers in ADPKD” offer valuable insights into the phenotypic variability and genetic complexity of ADPKD, while also identifying new therapeutic and diagnostic targets. Other clinical trials, such as the “Study of Tamibarotene in Patients With ADPKD”, “A Study of RGLS8429 in Patients with Autosomal Dominant Polycystic Kidney Disease” and “Study of Empagliflozin in Patients with Autosomal Dominant Polycystic Kidney Disease (EMPA-PKD)”, provide significant scientific insights for the development of therapeutic agents for ADPKD. By evaluating the safety and efficacy of these candidate drugs, these studies hold the potential to advance therapeutic innovations in the field, ultimately offering more effective treatment options for patients with ADPKD.
Table 1. Summary of PKD2 roles in organ development.
Table 1. Summary of PKD2 roles in organ development.
Different Function of PKD2Associated ProteinsPost Translational ModificationsBrief MechanismReference
Left–right asymmetryBicc1, Ccr4, Dand5, Nodal, Lefty2, Pitx2N/APKD2 regulates calcium signaling in the left-side cells of the LRO, leading to the degradation of Dand5 mRNA and the activation of nodal signaling, which ultimately establishes left–right asymmetry in internal organs.[45,46,47,48,49,50]
Regulation of intracellular calcium homeostasisRyanodine receptorsPhosphorylation of Ser812 by Casein Kinase IIPKD2 on cilia responds to mechanical signals, leading to calcium release from the endoplasmic reticulum via Ryanodine receptors.[74]
kidneys
Regulation of cell proliferation in kidneysAdenylyl cyclase 5/6, CREB, HEXIM1, cAMP, PKA, VEGF, ERKPhosphorylation of Ser158 of HEXIM1Decreased intracellular calcium in Pkd2 mutant kidneys reduces calcium-mediated inhibition of adenylyl cyclase, increasing cAMP levels, enhancing PKA activity, and stimulating cell proliferation.[77,78,79,80,81,82,83,84,85]
Interaction with transcription factorsID2, E2F, RbPhosphorylation of PKD2 (S812)Phosphorylated PKD2 interacts with ID2, preventing it from inhibiting p21 activation, leading to reduced CDK2 activity and enhanced cell proliferation through E2F transcription factors.[86,87,88]
Regulation of energy metabolismMitofusin 2 (MFN2)N/APKD2 regulates mitochondrial function and calcium transfer efficiency, enhancing respiration and promoting cell proliferation. Reduced MFN2 expression can restore mitochondrial calcium transfer.[89]
Maintenance of cell polarityβ-catenin, Axin2, c-Myc, E-cadherinN/AIn Pkd2 mutant mice, increased expression of β-catenin, Axin2, and c-Myc indicates disrupted canonical Wnt signaling. This disruption leads to elevated cytoplasmic β-catenin levels, which impede renal epithelial polarization due to loss of E-cadherin-mediated cell–cell contacts.[105]
Maintenance of renal structure in zebrafishScribble, GSK-3β, YAPPhosphorylation at the N-terminal site of Pkd2Pkd2 is located at the basal lateral membrane of the pronephric duct in zebrafish. Knockdown of Pkd2 reduces Scribble levels, inhibiting the Hippo signaling pathway and causing YAP to translocate to the nucleus, promoting glomerular cyst formation. Mislocalization affects structural integrity and function.[99]
Cardiovascular system
Regulation of valve formation in zebrafishCamk2g, Klf2aN/AIn zebrafish, early blood flow in the heart generates mechanical signals that are transduced by Pkd2 in atrioventricular endocardial cells. This regulates intracellular calcium ion concentration, activating Camk2g, which promotes Klf2a expression and valve formation.[38,106,107]
Regulation of cardiac calcium signalingRyR2, cardiac troponin I, phospholambanN/AIn mouse cardiomyocytes, PKD2 interacts with RyR2, inhibiting its channel activity in the presence of calcium. This leads to decreased calcium concentration in the sarcoplasmic reticulum, enhancing PKA-mediated phosphorylation of cardiac troponin I and reducing phospholamban dephosphorylation, which alters myocardial contractility.[180]
Cardiac protection during stressChromogranin B (CGB), ANP, BNPNot specifiedIn stressed mice, PKD2 levels increase, correlating with elevated left ventricular mass and natriuretic peptides (ANP and BNP). PKD2-deficient mice fail to upregulate protective atrial natriuretic peptide, leading to persistent elevated left ventricular mass after stress cessation.[112]
Regulation of vascular pressure through sensing mechanical forcesCalcium, calmodulin, protein kinase B, protein kinase C, α1-adrenoceptorsSUMOylationPKD2, located in cilia of vascular endothelial cells, senses fluid shear stress, activating a pathway that includes calcium influx and nitric oxide production, leading to vascular dilation and reduced blood pressure. In arterial myocytes, PKD2 channels are activated by intravascular pressure, inducing sodium currents that result in vasoconstriction. SUMO-PKD2 localization to the cell membrane is regulated by intravascular pressure, which stabilizes vascular pressure through controlling PKD2 abundance. In heterozygous Pkd2 mice, oxidative stress impairs relaxation function.[121,124]
Regulation of body axis developmentsec23A, sec23B, sec24C, sec24D, Pde1aN/ALoss of Pkd2 function in zebrafish leads to dorsal curvature of the body axis, potentially due to excessive type II collagen accumulation in notochord sheath cells. PKD2 maintains calcium ion homeostasis and modulates collagen gene expression through the phosphoinositide 3-kinase signaling pathway. Overexpression of Pde1a reduces cAMP levels, mitigating axial curvature.[154,155]

Funding

This research was funded by the National Natural Science Foundation of China (No. 32100661 to H.X. and No. 32200415 to Y.K.), the China Postdoctoral Science Foundation (No. 2023M733344 to H.X.), and the Taishan Scholar Foundation of Shandong Province (No. tsqn202312108 to H.X.).

Conflicts of Interest

The authors declare no conflicts of interests.

References

  1. Mochizuki, T.; Wu, G.; Hayashi, T.; Xenophontos, S.L.; Veldhuisen, B.; Saris, J.J.; Reynolds, D.M.; Cai, Y.; Gabow, P.A.; Pierides, A.; et al. PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 1996, 272, 1339–1342. [Google Scholar] [CrossRef] [PubMed]
  2. Shaw, C.; Simms, R.J.; Pitcher, D.; Sandford, R. Epidemiology of patients in England and Wales with autosomal dominant polycystic kidney disease and end-stage renal failure. Nephrol. Dial. Transplant. 2014, 29, 1910–1918. [Google Scholar] [CrossRef] [PubMed]
  3. Cornec-Le Gall, E.; Torres, V.E.; Harris, P.C. Genetic Complexity of Autosomal Dominant Polycystic Kidney and Liver Diseases. J. Am. Soc. Nephrol. 2018, 29, 13–23. [Google Scholar] [CrossRef]
  4. Chebib, F.T.; Torres, V.E. Autosomal Dominant Polycystic Kidney Disease: Core Curriculum 2016. Am. J. Kidney Dis. 2016, 67, 792–810. [Google Scholar] [CrossRef]
  5. Ong, A.C.; Ward, C.J.; Butler, R.J.; Biddolph, S.; Bowker, C.; Torra, R.; Pei, Y.; Harris, P.C. Coordinate expression of the autosomal dominant polycystic kidney disease proteins, polycystin-2 and polycystin-1, in normal and cystic tissue. Am. J. Pathol. 1999, 154, 1721–1729. [Google Scholar] [CrossRef] [PubMed]
  6. Mahboob, M.; Rout, P.; Leslie, S.W.; Bokhari, S.R.A. Autosomal Dominant Polycystic Kidney Disease. In StatPearls; StatPearls: Treasure Island, FL, USA, 2024. [Google Scholar]
  7. Zhang, M.; Ma, Y.; Ye, X.; Zhang, N.; Pan, L.; Wang, B. TRP (transient receptor potential) ion channel family: Structures, biological functions and therapeutic interventions for diseases. Signal Transduct. Target. Ther. 2023, 8, 261. [Google Scholar] [CrossRef]
  8. Grieben, M.; Pike, A.C.; Shintre, C.A.; Venturi, E.; El-Ajouz, S.; Tessitore, A.; Shrestha, L.; Mukhopadhyay, S.; Mahajan, P.; Chalk, R.; et al. Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nat. Struct. Mol. Biol. 2017, 24, 114–122. [Google Scholar] [CrossRef]
  9. Celic, A.; Petri, E.T.; Demeler, B.; Ehrlich, B.E.; Boggon, T.J. Domain mapping of the polycystin-2 C-terminal tail using de novo molecular modeling and biophysical analysis. J. Biol. Chem. 2008, 283, 28305–28312. [Google Scholar] [CrossRef]
  10. Cai, Y.; Maeda, Y.; Cedzich, A.; Torres, V.E.; Wu, G.; Hayashi, T.; Mochizuki, T.; Park, J.H.; Witzgall, R.; Somlo, S. Identification and characterization of polycystin-2, the PKD2 gene product. J. Biol. Chem. 1999, 274, 28557–28565. [Google Scholar] [CrossRef]
  11. Wilkes, M.; Madej, M.G.; Kreuter, L.; Rhinow, D.; Heinz, V.; De Sanctis, S.; Ruppel, S.; Richter, R.M.; Joos, F.; Grieben, M.; et al. Molecular insights into lipid-assisted Ca(2+) regulation of the TRP channel Polycystin-2. Nat. Struct. Mol. Biol. 2017, 24, 123–130. [Google Scholar] [CrossRef]
  12. Shen, P.S.; Yang, X.; DeCaen, P.G.; Liu, X.; Bulkley, D.; Clapham, D.E.; Cao, E. The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs. Cell 2016, 167, 763–773.e11. [Google Scholar] [CrossRef] [PubMed]
  13. Su, Q.; Hu, F.; Ge, X.; Lei, J.; Yu, S.; Wang, T.; Zhou, Q.; Mei, C.; Shi, Y. Structure of the human PKD1-PKD2 complex. Science 2018, 361, eaat9819. [Google Scholar] [CrossRef] [PubMed]
  14. Gonzalez-Perrett, S.; Kim, K.; Ibarra, C.; Damiano, A.E.; Zotta, E.; Batelli, M.; Harris, P.C.; Reisin, I.L.; Arnaout, M.A.; Cantiello, H.F. Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc. Natl. Acad. Sci. USA 2001, 98, 1182–1187. [Google Scholar] [CrossRef] [PubMed]
  15. Koulen, P.; Cai, Y.; Geng, L.; Maeda, Y.; Nishimura, S.; Witzgall, R.; Ehrlich, B.E.; Somlo, S. Polycystin-2 is an intracellular calcium release channel. Nat. Cell Biol. 2002, 4, 191–197. [Google Scholar] [CrossRef] [PubMed]
  16. Kleene, S.J.; Kleene, N.K. The native TRPP2-dependent channel of murine renal primary cilia. Am. J. Physiol. Renal Physiol. 2017, 312, F96–F108. [Google Scholar] [CrossRef]
  17. Liu, X.; Vien, T.; Duan, J.; Sheu, S.H.; DeCaen, P.G.; Clapham, D.E. Polycystin-2 is an essential ion channel subunit in the primary cilium of the renal collecting duct epithelium. Elife 2018, 7, 33183. [Google Scholar] [CrossRef]
  18. Kottgen, M.; Buchholz, B.; Garcia-Gonzalez, M.A.; Kotsis, F.; Fu, X.; Doerken, M.; Boehlke, C.; Steffl, D.; Tauber, R.; Wegierski, T.; et al. TRPP2 and TRPV4 form a polymodal sensory channel complex. J. Cell Biol. 2008, 182, 437–447. [Google Scholar] [CrossRef]
  19. Djenoune, L.; Mahamdeh, M.; Truong, T.V.; Nguyen, C.T.; Fraser, S.E.; Brueckner, M.; Howard, J.; Yuan, S. Cilia function as calcium-mediated mechanosensors that instruct left-right asymmetry. Science 2023, 379, 71–78. [Google Scholar] [CrossRef]
  20. Katoh, T.A.; Omori, T.; Mizuno, K.; Sai, X.; Minegishi, K.; Ikawa, Y.; Nishimura, H.; Itabashi, T.; Kajikawa, E.; Hiver, S.; et al. Immotile cilia mechanically sense the direction of fluid flow for left-right determination. Science 2023, 379, 66–71. [Google Scholar] [CrossRef]
  21. Chowdhury, P.; Sinha, D.; Poddar, A.; Chetluru, M.; Chen, Q. A mechanosensitive channel Pkd2 modulates the assembly of myosin II and actin filaments in the cytokinetic contractile ring. bioRxiv 2024. [Google Scholar] [CrossRef]
  22. Koyano, T.; Fujimoto, T.; Onishi, K.; Matsuyama, M.; Fukushima, M.; Kume, K. Pkd2, mutations linking to autosomal dominant polycystic kidney disease, localizes to the endoplasmic reticulum and regulates calcium signaling in fission yeast. Genes Cells 2023, 28, 811–820. [Google Scholar] [CrossRef] [PubMed]
  23. Malla, M.; Sinha, D.; Chowdhury, P.; Bisesi, B.T.; Chen, Q. The cytoplasmic tail of the mechanosensitive channel Pkd2 regulates its internalization and clustering in eisosomes. J. Cell Sci. 2023, 136, jcs260598. [Google Scholar] [CrossRef] [PubMed]
  24. Poddar, A.; Hsu, Y.Y.; Zhang, F.; Shamma, A.; Kreais, Z.; Muller, C.; Malla, M.; Ray, A.; Liu, A.P.; Chen, Q. Membrane stretching activates calcium permeability of a putative channel Pkd2 during fission yeast cytokinesis. Mol. Biol. Cell 2022, 33, ar134. [Google Scholar] [CrossRef] [PubMed]
  25. Sinha, D.; Ivan, D.; Gibbs, E.; Chetluru, M.; Goss, J.; Chen, Q. Correction: Fission yeast polycystin Pkd2p promotes cell size expansion and antagonizes the Hippo-related SIN pathway. J. Cell Sci. 2022, 135, jcs260446. [Google Scholar] [CrossRef]
  26. Morris, Z.; Sinha, D.; Poddar, A.; Morris, B.; Chen, Q. Fission yeast TRP channel Pkd2p localizes to the cleavage furrow and regulates cell separation during cytokinesis. Mol. Biol. Cell 2019, 30, 1791–1804. [Google Scholar] [CrossRef]
  27. Huang, J.; Tao, H.; Chen, J.; Shen, Y.; Lei, J.; Pan, J.; Yan, C.; Yan, N. Structure-guided discovery of protein and glycan components in native mastigonemes. Cell 2024, 187, 1733–1744.e12. [Google Scholar] [CrossRef]
  28. Das, P.; Mekonnen, B.; Alkhofash, R.; Ingle, A.V.; Workman, E.B.; Feather, A.; Zhang, G.; Chasen, N.; Liu, P.; Lechtreck, K.F. The Small Interactor of PKD2 protein promotes the assembly and ciliary entry of the Chlamydomonas PKD2-mastigoneme complexes. J. Cell Sci. 2024, 137, jcs261497. [Google Scholar] [CrossRef]
  29. Liu, P.; Lou, X.; Wingfield, J.L.; Lin, J.; Nicastro, D.; Lechtreck, K. Chlamydomonas PKD2 organizes mastigonemes, hair-like glycoprotein polymers on cilia. J. Cell Biol. 2020, 219, e202001122. [Google Scholar] [CrossRef]
  30. Huang, K.; Diener, D.R.; Mitchell, A.; Pazour, G.J.; Witman, G.B.; Rosenbaum, J.L. Function and dynamics of PKD2 in Chlamydomonas reinhardtii flagella. J. Cell Biol. 2007, 179, 501–514. [Google Scholar] [CrossRef]
  31. Sekimoto, H. Sexual reproduction and sex determination in green algae. J. Plant Res. 2017, 130, 423–431. [Google Scholar] [CrossRef]
  32. Bataille, S.; Demoulin, N.; Devuyst, O.; Audrezet, M.P.; Dahan, K.; Godin, M.; Fontes, M.; Pirson, Y.; Burtey, S. Association of PKD2 (polycystin 2) mutations with left-right laterality defects. Am. J. Kidney Dis. 2011, 58, 456–460. [Google Scholar] [CrossRef] [PubMed]
  33. Pennekamp, P.; Karcher, C.; Fischer, A.; Schweickert, A.; Skryabin, B.; Horst, J.; Blum, M.; Dworniczak, B. The ion channel polycystin-2 is required for left-right axis determination in mice. Curr. Biol. 2002, 12, 938–943. [Google Scholar] [CrossRef]
  34. Bisgrove, B.W.; Snarr, B.S.; Emrazian, A.; Yost, H.J. Polaris and Polycystin-2 in dorsal forerunner cells and Kupffer’s vesicle are required for specification of the zebrafish left-right axis. Dev. Biol. 2005, 287, 274–288. [Google Scholar] [CrossRef]
  35. Vick, P.; Kreis, J.; Schneider, I.; Tingler, M.; Getwan, M.; Thumberger, T.; Beyer, T.; Schweickert, A.; Blum, M. An Early Function of Polycystin-2 for Left-Right Organizer Induction in Xenopus. iScience 2018, 2, 76–85. [Google Scholar] [CrossRef] [PubMed]
  36. Pei, Y.; Watnick, T.; He, N.; Wang, K.; Liang, Y.; Parfrey, P.; Germino, G.; St George-Hyslop, P. Somatic PKD2 mutations in individual kidney and liver cysts support a “two-hit” model of cystogenesis in type 2 autosomal dominant polycystic kidney disease. J. Am. Soc. Nephrol. 1999, 10, 1524–1529. [Google Scholar] [CrossRef] [PubMed]
  37. Sun, Z.; Amsterdam, A.; Pazour, G.J.; Cole, D.G.; Miller, M.S.; Hopkins, N. A genetic screen in zebrafish identifies cilia genes as a principal cause of cystic kidney. Development 2004, 131, 4085–4093. [Google Scholar] [CrossRef]
  38. Juan, T.; Ribeiro da Silva, A.; Cardoso, B.; Lim, S.; Charteau, V.; Stainier, D.Y.R. Multiple pkd and piezo gene family members are required for atrioventricular valve formation. Nat. Commun. 2023, 14, 214. [Google Scholar] [CrossRef] [PubMed]
  39. Gao, Z.; Joseph, E.; Ruden, D.M.; Lu, X. Drosophila Pkd2 is haploid-insufficient for mediating optimal smooth muscle contractility. J. Biol. Chem. 2004, 279, 14225–14231. [Google Scholar] [CrossRef] [PubMed]
  40. Djenoune, L.; Berg, K.; Brueckner, M.; Yuan, S. A change of heart: New roles for cilia in cardiac development and disease. Nat. Rev. Cardiol. 2022, 19, 211–227. [Google Scholar] [CrossRef]
  41. Li, Y.; Klena, N.T.; Gabriel, G.C.; Liu, X.; Kim, A.J.; Lemke, K.; Chen, Y.; Chatterjee, B.; Devine, W.; Damerla, R.R.; et al. Global genetic analysis in mice unveils central role for cilia in congenital heart disease. Nature 2015, 521, 520–524. [Google Scholar] [CrossRef]
  42. Chen, Z.; Drummond, I.A. Polycystin-2, mechanosensing, and left-right asymmetry in autosomal dominant polycystic kidney disease. Kidney Int. 2023, 104, 638–640. [Google Scholar] [CrossRef] [PubMed]
  43. Shook, D.R.; Majer, C.; Keller, R. Pattern and morphogenesis of presumptive superficial mesoderm in two closely related species, Xenopus laevis and Xenopus tropicalis. Dev. Biol. 2004, 270, 163–185. [Google Scholar] [CrossRef]
  44. Little, R.B.; Norris, D.P. Right, left and cilia: How asymmetry is established. Semin. Cell Dev. Biol. 2021, 110, 11–18. [Google Scholar] [CrossRef] [PubMed]
  45. Yoshiba, S.; Shiratori, H.; Kuo, I.Y.; Kawasumi, A.; Shinohara, K.; Nonaka, S.; Asai, Y.; Sasaki, G.; Belo, J.A.; Sasaki, H.; et al. Cilia at the node of mouse embryos sense fluid flow for left-right determination via Pkd2. Science 2012, 338, 226–231. [Google Scholar] [CrossRef] [PubMed]
  46. Yuan, S.; Zhao, L.; Brueckner, M.; Sun, Z. Intraciliary calcium oscillations initiate vertebrate left-right asymmetry. Curr. Biol. 2015, 25, 556–567. [Google Scholar] [CrossRef]
  47. Mizuno, K.; Shiozawa, K.; Katoh, T.A.; Minegishi, K.; Ide, T.; Ikawa, Y.; Nishimura, H.; Takaoka, K.; Itabashi, T.; Iwane, A.H.; et al. Role of Ca(2+) transients at the node of the mouse embryo in breaking of left-right symmetry. Sci. Adv. 2020, 6, eaba1195. [Google Scholar] [CrossRef]
  48. Maerker, M.; Getwan, M.; Dowdle, M.E.; McSheene, J.C.; Gonzalez, V.; Pelliccia, J.L.; Hamilton, D.S.; Yartseva, V.; Vejnar, C.; Tingler, M.; et al. Bicc1 and Dicer regulate left-right patterning through post-transcriptional control of the Nodal inhibitor Dand5. Nat. Commun. 2021, 12, 5482. [Google Scholar] [CrossRef]
  49. Minegishi, K.; Rothe, B.; Komatsu, K.R.; Ono, H.; Ikawa, Y.; Nishimura, H.; Katoh, T.A.; Kajikawa, E.; Sai, X.; Miyashita, E.; et al. Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex. Nat. Commun. 2021, 12, 4071. [Google Scholar] [CrossRef]
  50. Takao, D.; Nemoto, T.; Abe, T.; Kiyonari, H.; Kajiura-Kobayashi, H.; Shiratori, H.; Nonaka, S. Asymmetric distribution of dynamic calcium signals in the node of mouse embryo during left-right axis formation. Dev. Biol. 2013, 376, 23–30. [Google Scholar] [CrossRef]
  51. Nakamura, T.; Hamada, H. Left-right patterning: Conserved and divergent mechanisms. Development 2012, 139, 3257–3262. [Google Scholar] [CrossRef]
  52. Rogers, K.W.; Lord, N.D.; Gagnon, J.A.; Pauli, A.; Zimmerman, S.; Aksel, D.C.; Reyon, D.; Tsai, S.Q.; Joung, J.K.; Schier, A.F. Nodal patterning without Lefty inhibitory feedback is functional but fragile. Elife 2017, 6, e28785. [Google Scholar] [CrossRef] [PubMed]
  53. Shiratori, H.; Hamada, H. The left-right axis in the mouse: From origin to morphology. Development 2006, 133, 2095–2104. [Google Scholar] [CrossRef] [PubMed]
  54. Ryan, A.K.; Blumberg, B.; Rodriguez-Esteban, C.; Yonei-Tamura, S.; Tamura, K.; Tsukui, T.; de la Pena, J.; Sabbagh, W.; Greenwald, J.; Choe, S.; et al. Pitx2 determines left-right asymmetry of internal organs in vertebrates. Nature 1998, 394, 545–551. [Google Scholar] [CrossRef] [PubMed]
  55. Shiratori, H.; Sakuma, R.; Watanabe, M.; Hashiguchi, H.; Mochida, K.; Sakai, Y.; Nishino, J.; Saijoh, Y.; Whitman, M.; Hamada, H. Two-step regulation of left-right asymmetric expression of Pitx2: Initiation by nodal signaling and maintenance by Nkx2. Mol. Cell 2001, 7, 137–149. [Google Scholar] [CrossRef]
  56. Piedra, M.E.; Icardo, J.M.; Albajar, M.; Rodriguez-Rey, J.C.; Ros, M.A. Pitx2 participates in the late phase of the pathway controlling left-right asymmetry. Cell 1998, 94, 319–324. [Google Scholar] [CrossRef]
  57. Yoshioka, H.; Meno, C.; Koshiba, K.; Sugihara, M.; Itoh, H.; Ishimaru, Y.; Inoue, T.; Ohuchi, H.; Semina, E.V.; Murray, J.C.; et al. Pitx2, a bicoid-type homeobox gene, is involved in a lefty-signaling pathway in determination of left-right asymmetry. Cell 1998, 94, 299–305. [Google Scholar] [CrossRef]
  58. Logan, M.; Pagan-Westphal, S.M.; Smith, D.M.; Paganessi, L.; Tabin, C.J. The transcription factor Pitx2 mediates situs-specific morphogenesis in response to left-right asymmetric signals. Cell 1998, 94, 307–317. [Google Scholar] [CrossRef]
  59. Shiratori, H.; Yashiro, K.; Shen, M.M.; Hamada, H. Conserved regulation and role of Pitx2 in situs-specific morphogenesis of visceral organs. Development 2006, 133, 3015–3025. [Google Scholar] [CrossRef]
  60. Bergmann, C.; Guay-Woodford, L.M.; Harris, P.C.; Horie, S.; Peters, D.J.M.; Torres, V.E. Polycystic kidney disease. Nat. Rev. Dis. Prim. 2018, 4, 50. [Google Scholar] [CrossRef]
  61. Koptides, M.; Deltas, C.C. Autosomal dominant polycystic kidney disease: Molecular genetics and molecular pathogenesis. Hum. Genet. 2000, 107, 115–126. [Google Scholar] [CrossRef]
  62. Happe, H.; Peters, D.J. Translational research in ADPKD: Lessons from animal models. Nat. Rev. Nephrol. 2014, 10, 587–601. [Google Scholar] [CrossRef]
  63. Sieben, C.J.; Harris, P.C. Experimental Models of Polycystic Kidney Disease: Applications and Therapeutic Testing. Kidney360 2023, 4, 1155–1173. [Google Scholar] [CrossRef] [PubMed]
  64. Lindstrom, N.O.; McMahon, J.A.; Guo, J.; Tran, T.; Guo, Q.; Rutledge, E.; Parvez, R.K.; Saribekyan, G.; Schuler, R.E.; Liao, C.; et al. Conserved and Divergent Features of Human and Mouse Kidney Organogenesis. J. Am. Soc. Nephrol. 2018, 29, 785–805. [Google Scholar] [CrossRef] [PubMed]
  65. Pennekamp, P.; Bogdanova, N.; Wilda, M.; Markoff, A.; Hameister, H.; Horst, J.; Dworniczak, B. Characterization of the murine polycystic kidney disease (Pkd2) gene. Mamm. Genome 1998, 9, 749–752. [Google Scholar] [CrossRef] [PubMed]
  66. Guillaume, R.; Trudel, M. Distinct and common developmental expression patterns of the murine Pkd2 and Pkd1 genes. Mech. Dev. 2000, 93, 179–183. [Google Scholar] [CrossRef] [PubMed]
  67. Yoder, B.K.; Hou, X.; Guay-Woodford, L.M. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol. 2002, 13, 2508–2516. [Google Scholar] [CrossRef]
  68. Nauli, S.M.; Alenghat, F.J.; Luo, Y.; Williams, E.; Vassilev, P.; Li, X.; Elia, A.E.; Lu, W.; Brown, E.M.; Quinn, S.J.; et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 2003, 33, 129–137. [Google Scholar] [CrossRef]
  69. Wu, G.; Markowitz, G.S.; Li, L.; D’Agati, V.D.; Factor, S.M.; Geng, L.; Tibara, S.; Tuchman, J.; Cai, Y.; Park, J.H.; et al. Cardiac defects and renal failure in mice with targeted mutations in Pkd2. Nat. Genet. 2000, 24, 75–78. [Google Scholar] [CrossRef]
  70. Lanner, J.T.; Georgiou, D.K.; Joshi, A.D.; Hamilton, S.L. Ryanodine receptors: Structure, expression, molecular details, and function in calcium release. Cold Spring Harb. Perspect Biol. 2010, 2, a003996. [Google Scholar] [CrossRef]
  71. Sammels, E.; Devogelaere, B.; Mekahli, D.; Bultynck, G.; Missiaen, L.; Parys, J.B.; Cai, Y.; Somlo, S.; De Smedt, H. Polycystin-2 activation by inositol 1,4,5-trisphosphate-induced Ca2+ release requires its direct association with the inositol 1,4,5-trisphosphate receptor in a signaling microdomain. J. Biol. Chem. 2010, 285, 18794–18805. [Google Scholar] [CrossRef]
  72. Padhy, B.; Xie, J.; Wang, R.; Lin, F.; Huang, C.L. Channel Function of Polycystin-2 in the Endoplasmic Reticulum Protects against Autosomal Dominant Polycystic Kidney Disease. J. Am. Soc. Nephrol. 2022, 33, 1501–1516. [Google Scholar] [CrossRef] [PubMed]
  73. Luo, Y.; Vassilev, P.M.; Li, X.; Kawanabe, Y.; Zhou, J. Native polycystin 2 functions as a plasma membrane Ca2+-permeable cation channel in renal epithelia. Mol. Cell. Biol. 2003, 23, 2600–2607. [Google Scholar] [CrossRef] [PubMed]
  74. Cai, Y.; Anyatonwu, G.; Okuhara, D.; Lee, K.B.; Yu, Z.; Onoe, T.; Mei, C.L.; Qian, Q.; Geng, L.; Wiztgall, R.; et al. Calcium dependence of polycystin-2 channel activity is modulated by phosphorylation at Ser812. J. Biol. Chem. 2004, 279, 19987–19995. [Google Scholar] [CrossRef] [PubMed]
  75. Chang, M.Y.; Parker, E.; Ibrahim, S.; Shortland, J.R.; Nahas, M.E.; Haylor, J.L.; Ong, A.C. Haploinsufficiency of Pkd2 is associated with increased tubular cell proliferation and interstitial fibrosis in two murine Pkd2 models. Nephrol. Dial Transplant. 2006, 21, 2078–2084. [Google Scholar] [CrossRef] [PubMed]
  76. Burtey, S.; Riera, M.; Ribe, E.; Pennekamp, P.; Passage, E.; Rance, R.; Dworniczak, B.; Fontes, M. Overexpression of PKD2 in the mouse is associated with renal tubulopathy. Nephrol. Dial Transplant. 2008, 23, 1157–1165. [Google Scholar] [CrossRef]
  77. Belibi, F.A.; Reif, G.; Wallace, D.P.; Yamaguchi, T.; Olsen, L.; Li, H.; Helmkamp, G.M., Jr.; Grantham, J.J. Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells. Kidney Int. 2004, 66, 964–973. [Google Scholar] [CrossRef]
  78. Yamaguchi, T.; Pelling, J.C.; Ramaswamy, N.T.; Eppler, J.W.; Wallace, D.P.; Nagao, S.; Rome, L.A.; Sullivan, L.P.; Grantham, J.J. cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int. 2000, 57, 1460–1471. [Google Scholar] [CrossRef]
  79. Yanda, M.K.; Liu, Q.; Cebotaru, V.; Guggino, W.B.; Cebotaru, L. Role of calcium in adult onset polycystic kidney disease. Cell Signal. 2019, 53, 140–150. [Google Scholar] [CrossRef]
  80. Ortiz-Capisano, M.C.; Ortiz, P.A.; Harding, P.; Garvin, J.L.; Beierwaltes, W.H. Decreased intracellular calcium stimulates renin release via calcium-inhibitable adenylyl cyclase. Hypertension 2007, 49, 162–169. [Google Scholar] [CrossRef]
  81. Spirli, C.; Okolicsanyi, S.; Fiorotto, R.; Fabris, L.; Cadamuro, M.; Lecchi, S.; Tian, X.; Somlo, S.; Strazzabosco, M. ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice. Gastroenterology 2010, 138, 360–371.e7. [Google Scholar] [CrossRef]
  82. Liu, Z.; Liu, Y.; Dang, L.; Geng, M.; Sun, Y.; Lu, Y.; Fang, Z.; Xiong, H.; Chen, Y. Integrative Cistromic and Transcriptomic Analyses Identify CREB Target Genes in Cystic Renal Epithelial Cells. J. Am. Soc. Nephrol. 2021, 32, 2529–2541. [Google Scholar] [CrossRef] [PubMed]
  83. Sun, Y.; Liu, Z.; Cao, X.; Lu, Y.; Mi, Z.; He, C.; Liu, J.; Zheng, Z.; Li, M.J.; Li, T.; et al. Activation of P-TEFb by cAMP-PKA signaling in autosomal dominant polycystic kidney disease. Sci. Adv. 2019, 5, eaaw3593. [Google Scholar] [CrossRef] [PubMed]
  84. Burtey, S.; Riera, M.; Ribe, E.; Pennenkamp, P.; Rance, R.; Luciani, J.; Dworniczak, B.; Mattei, M.G.; Fontes, M. Centrosome overduplication and mitotic instability in PKD2 transgenic lines. Cell Biol. Int. 2008, 32, 1193–1198. [Google Scholar] [CrossRef]
  85. Park, E.Y.; Sung, Y.H.; Yang, M.H.; Noh, J.Y.; Park, S.Y.; Lee, T.Y.; Yook, Y.J.; Yoo, K.H.; Roh, K.J.; Kim, I.; et al. Cyst formation in kidney via B-Raf signaling in the PKD2 transgenic mice. J. Biol. Chem. 2009, 284, 7214–7222. [Google Scholar] [CrossRef] [PubMed]
  86. Li, X.; Luo, Y.; Starremans, P.G.; McNamara, C.A.; Pei, Y.; Zhou, J. Polycystin-1 and polycystin-2 regulate the cell cycle through the helix-loop-helix inhibitor Id2. Nat. Cell Biol. 2005, 7, 1202–1212. [Google Scholar] [CrossRef]
  87. Bhunia, A.K.; Piontek, K.; Boletta, A.; Liu, L.; Qian, F.; Xu, P.N.; Germino, F.J.; Germino, G.G. PKD1 induces p21(waf1) and regulation of the cell cycle via direct activation of the JAK-STAT signaling pathway in a process requiring PKD2. Cell 2002, 109, 157–168. [Google Scholar] [CrossRef]
  88. Fan, L.X.; Li, X.; Magenheimer, B.; Calvet, J.P.; Li, X. Inhibition of histone deacetylases targets the transcription regulator Id2 to attenuate cystic epithelial cell proliferation. Kidney Int. 2012, 81, 76–85. [Google Scholar] [CrossRef]
  89. Kuo, I.Y.; Brill, A.L.; Lemos, F.O.; Jiang, J.Y.; Falcone, J.L.; Kimmerling, E.P.; Cai, Y.; Dong, K.; Kaplan, D.L.; Wallace, D.P.; et al. Polycystin 2 regulates mitochondrial Ca2+ signaling, bioenergetics, and dynamics through mitofusin 2. Sci. Signal. 2019, 12, aat7397. [Google Scholar] [CrossRef]
  90. Rowe, I.; Chiaravalli, M.; Mannella, V.; Ulisse, V.; Quilici, G.; Pema, M.; Song, X.W.; Xu, H.; Mari, S.; Qian, F.; et al. Defective glucose metabolism in polycystic kidney disease identifies a new therapeutic strategy. Nat. Med. 2013, 19, 488–493. [Google Scholar] [CrossRef]
  91. Inoki, K.; Zhu, T.; Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115, 577–590. [Google Scholar] [CrossRef]
  92. Kim, I.; Ding, T.; Fu, Y.; Li, C.; Cui, L.; Li, A.; Lian, P.; Liang, D.; Wang, D.W.; Guo, C.; et al. Conditional mutation of Pkd2 causes cystogenesis and upregulates beta-catenin. J. Am. Soc. Nephrol. 2009, 20, 2556–2569. [Google Scholar] [CrossRef] [PubMed]
  93. Besschetnova, T.Y.; Kolpakova-Hart, E.; Guan, Y.; Zhou, J.; Olsen, B.R.; Shah, J.V. Identification of signaling pathways regulating primary cilium length and flow-mediated adaptation. Curr. Biol. 2010, 20, 182–187. [Google Scholar] [CrossRef] [PubMed]
  94. Ma, M.; Tian, X.; Igarashi, P.; Pazour, G.J.; Somlo, S. Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease. Nat. Genet. 2013, 45, 1004–1012. [Google Scholar] [CrossRef] [PubMed]
  95. Mazloum, M.; Lapin, B.; Viau, A.; Alghamdi, R.; Burtin, M.; Houillier, P.; Cheval, L.; Crambert, G.; Aka, A.; Kuehn, E.W.; et al. Cilia to basement membrane signalling is a biomechanical driver of autosomal dominant polycystic kidney disease. bioRxiv 2024. [Google Scholar]
  96. Obara, T.; Mangos, S.; Liu, Y.; Zhao, J.; Wiessner, S.; Kramer-Zucker, A.G.; Olale, F.; Schier, A.F.; Drummond, I.A. Polycystin-2 immunolocalization and function in zebrafish. J. Am. Soc. Nephrol. 2006, 17, 2706–2718. [Google Scholar] [CrossRef] [PubMed]
  97. Schottenfeld, J.; Sullivan-Brown, J.; Burdine, R.D. Zebrafish curly up encodes a Pkd2 ortholog that restricts left-side-specific expression of southpaw. Development 2007, 134, 1605–1615. [Google Scholar] [CrossRef]
  98. Sullivan-Brown, J.; Schottenfeld, J.; Okabe, N.; Hostetter, C.L.; Serluca, F.C.; Thiberge, S.Y.; Burdine, R.D. Zebrafish mutations affecting cilia motility share similar cystic phenotypes and suggest a mechanism of cyst formation that differs from pkd2 morphants. Dev. Biol. 2008, 314, 261–275. [Google Scholar] [CrossRef]
  99. Xu, D.; Lv, J.; He, L.; Fu, L.; Hu, R.; Cao, Y.; Mei, C. Scribble influences cyst formation in autosomal-dominant polycystic kidney disease by regulating Hippo signaling pathway. FASEB J. 2018, 32, 4394–4407. [Google Scholar] [CrossRef]
  100. Streets, A.J.; Moon, D.J.; Kane, M.E.; Obara, T.; Ong, A.C. Identification of an N-terminal glycogen synthase kinase 3 phosphorylation site which regulates the functional localization of polycystin-2 in vivo and in vitro. Hum. Mol. Genet. 2006, 15, 1465–1473. [Google Scholar] [CrossRef]
  101. Fu, X.; Wang, Y.; Schetle, N.; Gao, H.; Putz, M.; von Gersdorff, G.; Walz, G.; Kramer-Zucker, A.G. The subcellular localization of TRPP2 modulates its function. J. Am. Soc. Nephrol. 2008, 19, 1342–1351. [Google Scholar] [CrossRef]
  102. Sans-Atxer, L.; Joly, D. Tolvaptan in the treatment of autosomal dominant polycystic kidney disease: Patient selection and special considerations. Int. J. Nephrol. Renovasc. Dis. 2018, 11, 41–51. [Google Scholar] [CrossRef] [PubMed]
  103. Lantinga, M.A.; D’Agnolo, H.M.; Casteleijn, N.F.; de Fijter, J.W.; Meijer, E.; Messchendorp, A.L.; Peters, D.J.; Salih, M.; Spithoven, E.M.; Soonawala, D.; et al. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study. Drug Saf. 2017, 40, 153–167. [Google Scholar] [CrossRef]
  104. Ruggenenti, P.; Gentile, G.; Perico, N.; Perna, A.; Barcella, L.; Trillini, M.; Cortinovis, M.; Ferrer Siles, C.P.; Reyes Loaeza, J.A.; Aparicio, M.C.; et al. Effect of Sirolimus on Disease Progression in Patients with Autosomal Dominant Polycystic Kidney Disease and CKD Stages 3b-4. Clin. J. Am. Soc. Nephrol. 2016, 11, 785–794. [Google Scholar] [CrossRef] [PubMed]
  105. Li, A.; Xu, Y.; Fan, S.; Meng, J.; Shen, X.; Xiao, Q.; Li, Y.; Zhang, L.; Zhang, X.; Wu, G.; et al. Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD. JCI Insight 2018, 3, e95874. [Google Scholar] [CrossRef] [PubMed]
  106. Heckel, E.; Boselli, F.; Roth, S.; Krudewig, A.; Belting, H.G.; Charvin, G.; Vermot, J. Oscillatory Flow Modulates Mechanosensitive klf2a Expression through trpv4 and trpp2 during Heart Valve Development. Curr. Biol. 2015, 25, 1354–1361. [Google Scholar] [CrossRef]
  107. Vermot, J.; Forouhar, A.S.; Liebling, M.; Wu, D.; Plummer, D.; Gharib, M.; Fraser, S.E. Reversing blood flows act through klf2a to ensure normal valvulogenesis in the developing heart. PLoS Biol. 2009, 7, e1000246. [Google Scholar] [CrossRef]
  108. Anyatonwu, G.I.; Estrada, M.; Tian, X.; Somlo, S.; Ehrlich, B.E. Regulation of ryanodine receptor-dependent calcium signaling by polycystin-2. Proc. Natl. Acad. Sci. USA 2007, 104, 6454–6459. [Google Scholar] [CrossRef]
  109. Kuo, I.Y.; Kwaczala, A.T.; Nguyen, L.; Russell, K.S.; Campbell, S.G.; Ehrlich, B.E. Decreased polycystin 2 expression alters calcium-contraction coupling and changes beta-adrenergic signaling pathways. Proc. Natl. Acad. Sci. USA 2014, 111, 16604–16609. [Google Scholar] [CrossRef] [PubMed]
  110. Paavola, J.; Schliffke, S.; Rossetti, S.; Kuo, I.Y.; Yuan, S.; Sun, Z.; Harris, P.C.; Torres, V.E.; Ehrlich, B.E. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J. Mol. Cell Cardiol. 2013, 58, 199–208. [Google Scholar] [CrossRef]
  111. Sang, D.; Bai, S.; Yin, S.; Jiang, S.; Ye, L.; Hou, W.; Yao, Y.; Wang, H.; Shen, Y.; Shen, B.; et al. Role of TRPP2 in mouse airway smooth muscle tension and respiration. Am. J. Physiol. Lung Cell Mol. Physiol. 2019, 317, L466–L474. [Google Scholar] [CrossRef]
  112. Giehl, E.; Lemos, F.O.; Huang, Y.; Giordano, F.J.; Kuo, I.Y.; Ehrlich, B.E. Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress. Pflugers Arch. 2017, 469, 1507–1517. [Google Scholar] [CrossRef] [PubMed]
  113. Torres, V.E.; Cai, Y.; Chen, X.I.; Wu, G.Q.; Geng, L.; Cleghorn, K.A.; Johnson, C.M.; Somlo, S. Vascular expression of polycystin-2. J. Am. Soc. Nephrol. 2001, 12, 1–9. [Google Scholar] [CrossRef] [PubMed]
  114. Qian, Q.; Li, M.; Cai, Y.; Ward, C.J.; Somlo, S.; Harris, P.C.; Torres, V.E. Analysis of the polycystins in aortic vascular smooth muscle cells. J. Am. Soc. Nephrol. 2003, 14, 2280–2287. [Google Scholar] [CrossRef]
  115. AbouAlaiwi, W.A.; Takahashi, M.; Mell, B.R.; Jones, T.J.; Ratnam, S.; Kolb, R.J.; Nauli, S.M. Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circ. Res. 2009, 104, 860–869. [Google Scholar] [CrossRef] [PubMed]
  116. Dennis, M.R.; Pires, P.W.; Banek, C.T. Vascular Dysfunction in Polycystic Kidney Disease: A Mini-Review. J. Vasc. Res. 2023, 60, 125–136. [Google Scholar] [CrossRef]
  117. Brookes, Z.L.; Ruff, L.; Upadhyay, V.S.; Huang, L.; Prasad, S.; Solanky, T.; Nauli, S.M.; Ong, A.C. Pkd2 mesenteric vessels exhibit a primary defect in endothelium-dependent vasodilatation restored by rosiglitazone. Am. J. Physiol. Heart Circ. Physiol. 2013, 304, H33–H41. [Google Scholar] [CrossRef] [PubMed]
  118. Outeda, P.; Huso, D.L.; Fisher, S.A.; Halushka, M.K.; Kim, H.; Qian, F.; Germino, G.G.; Watnick, T. Polycystin signaling is required for directed endothelial cell migration and lymphatic development. Cell Rep. 2014, 7, 634–644. [Google Scholar] [CrossRef]
  119. Goetz, J.G.; Steed, E.; Ferreira, R.R.; Roth, S.; Ramspacher, C.; Boselli, F.; Charvin, G.; Liebling, M.; Wyart, C.; Schwab, Y.; et al. Endothelial cilia mediate low flow sensing during zebrafish vascular development. Cell Rep. 2014, 6, 799–808. [Google Scholar] [CrossRef]
  120. Campinho, P.; Lamperti, P.; Boselli, F.; Vilfan, A.; Vermot, J. Blood Flow Limits Endothelial Cell Extrusion in the Zebrafish Dorsal Aorta. Cell Rep. 2020, 31, 107505. [Google Scholar] [CrossRef]
  121. MacKay, C.E.; Leo, M.D.; Fernandez-Pena, C.; Hasan, R.; Yin, W.; Mata-Daboin, A.; Bulley, S.; Gammons, J.; Mancarella, S.; Jaggar, J.H. Intravascular flow stimulates PKD2 (polycystin-2) channels in endothelial cells to reduce blood pressure. Elife 2020, 9, e56655. [Google Scholar] [CrossRef]
  122. MacKay, C.E.; Floen, M.; Leo, M.D.; Hasan, R.; Garrud, T.A.C.; Fernandez-Pena, C.; Singh, P.; Malik, K.U.; Jaggar, J.H. A plasma membrane-localized polycystin-1/polycystin-2 complex in endothelial cells elicits vasodilation. Elife 2022, 11, e74765. [Google Scholar] [CrossRef] [PubMed]
  123. Bulley, S.; Fernandez-Pena, C.; Hasan, R.; Leo, M.D.; Muralidharan, P.; MacKay, C.E.; Evanson, K.W.; Moreira-Junior, L.; Mata-Daboin, A.; Burris, S.K.; et al. Correction: Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure. Elife 2020, 9, e60403. [Google Scholar] [CrossRef] [PubMed]
  124. Hasan, R.; Leo, M.D.; Muralidharan, P.; Mata-Daboin, A.; Yin, W.; Bulley, S.; Fernandez-Pena, C.; MacKay, C.E.; Jaggar, J.H. SUMO1 modification of PKD2 channels regulates arterial contractility. Proc. Natl. Acad. Sci. USA 2019, 116, 27095–27104. [Google Scholar] [CrossRef] [PubMed]
  125. Nakano, K.; Sukegawa, G.; Tsuji, Y. Secondary infertility due to necrospermia in men with autosomal-dominant polycystic kidney disease: A report of two cases. CEN Case Rep. 2024. preprint. [Google Scholar] [CrossRef] [PubMed]
  126. Luciano, R.L.; Dahl, N.K. Extra-renal manifestations of autosomal dominant polycystic kidney disease (ADPKD): Considerations for routine screening and management. Nephrol. Dial Transplant. 2014, 29, 247–254. [Google Scholar] [CrossRef]
  127. Nie, X.; Arend, L.J. Novel roles of Pkd2 in male reproductive system development. Differentiation 2014, 87, 161–171. [Google Scholar] [CrossRef]
  128. Watnick, T.J.; Jin, Y.; Matunis, E.; Kernan, M.J.; Montell, C. A flagellar polycystin-2 homolog required for male fertility in Drosophila. Curr. Biol. 2003, 13, 2179–2184. [Google Scholar] [CrossRef]
  129. Gao, Z.; Ruden, D.M.; Lu, X. PKD2 cation channel is required for directional sperm movement and male fertility. Curr. Biol. 2003, 13, 2175–2178. [Google Scholar] [CrossRef]
  130. Kottgen, M.; Hofherr, A.; Li, W.; Chu, K.; Cook, S.; Montell, C.; Watnick, T. Drosophila sperm swim backwards in the female reproductive tract and are activated via TRPP2 ion channels. PLoS ONE 2011, 6, e20031. [Google Scholar] [CrossRef]
  131. Yang, Y.; Lu, X. Drosophila sperm motility in the reproductive tract. Biol. Reprod. 2011, 84, 1005–1015. [Google Scholar] [CrossRef]
  132. Yang, Y.; Cochran, D.A.; Gargano, M.D.; King, I.; Samhat, N.K.; Burger, B.P.; Sabourin, K.R.; Hou, Y.; Awata, J.; Parry, D.A.; et al. Regulation of flagellar motility by the conserved flagellar protein CG34110/Ccdc135/FAP50. Mol. Biol. Cell 2011, 22, 976–987. [Google Scholar] [CrossRef] [PubMed]
  133. Barr, M.M.; DeModena, J.; Braun, D.; Nguyen, C.Q.; Hall, D.H.; Sternberg, P.W. The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr. Biol. 2001, 11, 1341–1346. [Google Scholar] [CrossRef] [PubMed]
  134. Lints, R.; Emmons, S.W. Regulation of sex-specific differentiation and mating behavior in C. elegans by a new member of the DM domain transcription factor family. Genes Dev. 2002, 16, 2390–2402. [Google Scholar] [CrossRef] [PubMed]
  135. Knobel, K.M.; Peden, E.M.; Barr, M.M. Distinct protein domains regulate ciliary targeting and function of C. elegans PKD-2. Exp. Cell Res. 2008, 314, 825–833. [Google Scholar] [CrossRef]
  136. Bae, Y.K.; Qin, H.; Knobel, K.M.; Hu, J.; Rosenbaum, J.L.; Barr, M.M. General and cell-type specific mechanisms target TRPP2/PKD-2 to cilia. Development 2006, 133, 3859–3870. [Google Scholar] [CrossRef]
  137. Liu, K.S.; Sternberg, P.W. Sensory regulation of male mating behavior in Caenorhabditis elegans. Neuron 1995, 14, 79–89. [Google Scholar] [CrossRef]
  138. Barr, M.M.; Sternberg, P.W. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature 1999, 401, 386–389. [Google Scholar] [CrossRef]
  139. Chasnov, J.R.; So, W.K.; Chan, C.M.; Chow, K.L. The species, sex, and stage specificity of a Caenorhabditis sex pheromone. Proc. Natl. Acad. Sci. USA 2007, 104, 6730–6735. [Google Scholar] [CrossRef]
  140. Wang, J.; Silva, M.; Haas, L.A.; Morsci, N.S.; Nguyen, K.C.; Hall, D.H.; Barr, M.M. C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication. Curr. Biol. 2014, 24, 519–525. [Google Scholar] [CrossRef]
  141. Wang, J.; Nikonorova, I.A.; Gu, A.; Sternberg, P.W.; Barr, M.M. Release and targeting of polycystin-2-carrying ciliary extracellular vesicles. Curr. Biol. 2020, 30, R755–R756. [Google Scholar] [CrossRef]
  142. Wang, J.; Nikonorova, I.A.; Silva, M.; Walsh, J.D.; Tilton, P.E.; Gu, A.; Akella, J.S.; Barr, M.M. Sensory cilia act as a specialized venue for regulated extracellular vesicle biogenesis and signaling. Curr. Biol. 2021, 31, 3943–3951.e3. [Google Scholar] [CrossRef] [PubMed]
  143. Wang, J.; Kaletsky, R.; Silva, M.; Williams, A.; Haas, L.A.; Androwski, R.J.; Landis, J.N.; Patrick, C.; Rashid, A.; Santiago-Martinez, D.; et al. Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis. Curr. Biol. 2015, 25, 3232–3238. [Google Scholar] [CrossRef] [PubMed]
  144. Qin, H.; Burnette, D.T.; Bae, Y.K.; Forscher, P.; Barr, M.M.; Rosenbaum, J.L. Intraflagellar transport is required for the vectorial movement of TRPV channels in the ciliary membrane. Curr. Biol. 2005, 15, 1695–1699. [Google Scholar] [CrossRef]
  145. Li, Y.; Zhang, Q.; Wei, Q.; Zhang, Y.; Ling, K.; Hu, J. SUMOylation of the small GTPase ARL-13 promotes ciliary targeting of sensory receptors. J. Cell Biol. 2012, 199, 589–598. [Google Scholar] [CrossRef]
  146. Peden, E.M.; Barr, M.M. The KLP-6 kinesin is required for male mating behaviors and polycystin localization in Caenorhabditis elegans. Curr. Biol. 2005, 15, 394–404. [Google Scholar] [CrossRef] [PubMed]
  147. Hu, J.; Bae, Y.K.; Knobel, K.M.; Barr, M.M. Casein kinase II and calcineurin modulate TRPP function and ciliary localization. Mol. Biol. Cell 2006, 17, 2200–2211. [Google Scholar] [CrossRef]
  148. Bae, Y.K.; Lyman-Gingerich, J.; Barr, M.M.; Knobel, K.M. Identification of genes involved in the ciliary trafficking of C. elegans PKD-2. Dev. Dyn. 2008, 237, 2021–2029. [Google Scholar] [CrossRef]
  149. Bae, Y.K.; Kim, E.; L’Hernault, S.W.; Barr, M.M. The CIL-1 PI 5-phosphatase localizes TRP Polycystins to cilia and activates sperm in C. elegans. Curr. Biol. 2009, 19, 1599–1607. [Google Scholar] [CrossRef]
  150. Hu, J.; Wittekind, S.G.; Barr, M.M. STAM and Hrs down-regulate ciliary TRP receptors. Mol. Biol. Cell 2007, 18, 3277–3289. [Google Scholar] [CrossRef]
  151. Yu, H.; Pretot, R.F.; Burglin, T.R.; Sternberg, P.W. Distinct roles of transcription factors EGL-46 and DAF-19 in specifying the functionality of a polycystin-expressing sensory neuron necessary for C. elegans male vulva location behavior. Development 2003, 130, 5217–5227. [Google Scholar] [CrossRef]
  152. O’Hagan, R.; Silva, M.; Nguyen, K.C.Q.; Zhang, W.; Bellotti, S.; Ramadan, Y.H.; Hall, D.H.; Barr, M.M. Glutamylation Regulates Transport, Specializes Function, and Sculpts the Structure of Cilia. Curr. Biol. 2017, 27, 3430–3441.e6. [Google Scholar] [CrossRef] [PubMed]
  153. Scheidel, N.; Kennedy, J.; Blacque, O.E. Endosome maturation factors Rabenosyn-5/VPS45 and caveolin-1 regulate ciliary membrane and polycystin-2 homeostasis. EMBO J. 2018, 37, e98248. [Google Scholar] [CrossRef] [PubMed]
  154. Mangos, S.; Lam, P.Y.; Zhao, A.; Liu, Y.; Mudumana, S.; Vasilyev, A.; Liu, A.; Drummond, I.A. The ADPKD genes pkd1a/b and pkd2 regulate extracellular matrix formation. Dis. Model. Mech. 2010, 3, 354–365. [Google Scholar] [CrossRef] [PubMed]
  155. Le Corre, S.; Eyre, D.; Drummond, I.A. Modulation of the secretory pathway rescues zebrafish polycystic kidney disease pathology. J. Am. Soc. Nephrol. 2014, 25, 1749–1759. [Google Scholar] [CrossRef]
  156. Sussman, C.R.; Ward, C.J.; Leightner, A.C.; Smith, J.L.; Agarwal, R.; Harris, P.C.; Torres, V.E. Phosphodiesterase 1A modulates cystogenesis in zebrafish. J. Am. Soc. Nephrol. 2014, 25, 2222–2230. [Google Scholar] [CrossRef]
  157. Cao, Y.; Semanchik, N.; Lee, S.H.; Somlo, S.; Barbano, P.E.; Coifman, R.; Sun, Z. Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc. Natl. Acad. Sci. USA 2009, 106, 21819–21824. [Google Scholar] [CrossRef]
  158. Metzner, A.; Griffiths, J.D.; Streets, A.J.; Markham, E.; Philippou, T.; Van Eeden, F.J.M.; Ong, A.C.M. A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2(−/−) phenotype. Sci. Rep. 2020, 10, 72. [Google Scholar] [CrossRef]
  159. Khonsari, R.H.; Ohazama, A.; Raouf, R.; Kawasaki, M.; Kawasaki, K.; Porntaveetus, T.; Ghafoor, S.; Hammond, P.; Suttie, M.; Odri, G.A.; et al. Multiple postnatal craniofacial anomalies are characterized by conditional loss of polycystic kidney disease 2 (Pkd2). Hum. Mol. Genet. 2013, 22, 1873–1885. [Google Scholar] [CrossRef]
  160. Xiao, Z.; Cao, L.; Liang, Y.; Huang, J.; Stern, A.R.; Dallas, M.; Johnson, M.; Quarles, L.D. Osteoblast-specific deletion of Pkd2 leads to low-turnover osteopenia and reduced bone marrow adiposity. PLoS ONE 2014, 9, e114198. [Google Scholar] [CrossRef]
  161. Turner, H.N.; Armengol, K.; Patel, A.A.; Himmel, N.J.; Sullivan, L.; Iyer, S.C.; Bhattacharya, S.; Iyer, E.P.R.; Landry, C.; Galko, M.J.; et al. The TRP Channels Pkd2, NompC, and Trpm Act in Cold-Sensing Neurons to Mediate Unique Aversive Behaviors to Noxious Cold in Drosophila. Curr. Biol. 2016, 26, 3116–3128. [Google Scholar] [CrossRef]
  162. Bezares-Calderon, L.A.; Berger, J.; Jasek, S.; Veraszto, C.; Mendes, S.; Guhmann, M.; Almeda, R.; Shahidi, R.; Jekely, G. Neural circuitry of a polycystin-mediated hydrodynamic startle response for predator avoidance. Elife 2018, 7, e36262. [Google Scholar] [CrossRef] [PubMed]
  163. Ohata, S.; Herranz-Perez, V.; Nakatani, J.; Boletta, A.; Garcia-Verdugo, J.M.; Alvarez-Buylla, A. Mechanosensory Genes Pkd1 and Pkd2 Contribute to the Planar Polarization of Brain Ventricular Epithelium. J. Neurosci. 2015, 35, 11153–11168. [Google Scholar] [CrossRef] [PubMed]
  164. Winokurow, N.; Schumacher, S. A role for polycystin-1 and polycystin-2 in neural progenitor cell differentiation. Cell Mol. Life Sci. 2019, 76, 2851–2869. [Google Scholar] [CrossRef] [PubMed]
  165. Lanktree, M.B.; Haghighi, A.; Guiard, E.; Iliuta, I.A.; Song, X.; Harris, P.C.; Paterson, A.D.; Pei, Y. Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing. J. Am. Soc. Nephrol. 2018, 29, 2593–2600. [Google Scholar] [CrossRef]
  166. Fedeles, S.V.; Tian, X.; Gallagher, A.R.; Mitobe, M.; Nishio, S.; Lee, S.H.; Cai, Y.; Geng, L.; Crews, C.M.; Somlo, S. A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation. Nat. Genet. 2011, 43, 639–647. [Google Scholar] [CrossRef]
  167. Kleffmann, J.; Frank, V.; Ferbert, A.; Bergmann, C. Dosage-sensitive network in polycystic kidney and liver disease: Multiple mutations cause severe hepatic and neurological complications. J. Hepatol. 2012, 57, 476–477. [Google Scholar] [CrossRef]
  168. Roth, C.; Kleffmann, J.; Bergmann, C.; Deinsberger, W.; Ferbert, A. Ruptured cerebral aneurysm and acute bilateral carotid artery dissection in a patient with polycystic kidney disease and polycystic liver disease. Cerebrovasc. Dis. 2013, 35, 590–591. [Google Scholar] [CrossRef]
  169. Ramsdell, A.F. Left-right asymmetry and congenital cardiac defects: Getting to the heart of the matter in vertebrate left-right axis determination. Dev. Biol. 2005, 288, 1–20. [Google Scholar] [CrossRef]
  170. Yang, D.; Jian, Z.; Tang, C.; Chen, Z.; Zhou, Z.; Zheng, L.; Peng, X. Zebrafish Congenital Heart Disease Models: Opportunities and Challenges. Int. J. Mol. Sci. 2024, 25, 5943. [Google Scholar] [CrossRef]
  171. Kim, I.; Li, C.; Liang, D.; Chen, X.Z.; Coffy, R.J.; Ma, J.; Zhao, P.; Wu, G. Polycystin-2 expression is regulated by a PC2-binding domain in the intracellular portion of fibrocystin. J. Biol. Chem. 2008, 283, 31559–31566. [Google Scholar] [CrossRef]
  172. Stroope, A.; Radtke, B.; Huang, B.; Masyuk, T.; Torres, V.; Ritman, E.; LaRusso, N. Hepato-renal pathology in pkd2ws25/- mice, an animal model of autosomal dominant polycystic kidney disease. Am. J. Pathol. 2010, 176, 1282–1291. [Google Scholar] [CrossRef] [PubMed]
  173. Nagao, S.; Yamaguchi, T. Review of the Use of Animal Models of Human Polycystic Kidney Disease for the Evaluation of Experimental Therapeutic Modalities. J. Clin. Med. 2023, 12, 668. [Google Scholar] [CrossRef] [PubMed]
  174. Elmonem, M.A.; Berlingerio, S.P.; van den Heuvel, L.P.; de Witte, P.A.; Lowe, M.; Levtchenko, E.N. Genetic Renal Diseases: The Emerging Role of Zebrafish Models. Cells 2018, 7, 130. [Google Scholar] [CrossRef]
  175. Gehrig, J.; Pandey, G.; Westhoff, J.H. Zebrafish as a Model for Drug Screening in Genetic Kidney Diseases. Front. Pediatr. 2018, 6, 183. [Google Scholar] [CrossRef] [PubMed]
  176. Strange, K. Drug Discovery in Fish, Flies, and Worms. ILAR J. 2016, 57, 133–143. [Google Scholar] [CrossRef]
  177. Vishy, C.E.; Thomas, C.; Vincent, T.; Crawford, D.K.; Goddeeris, M.M.; Freedman, B.S. Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease. Cell Stem Cell 2024, 31, 537–553.e5. [Google Scholar] [CrossRef]
  178. Shimizu, T.; Mae, S.I.; Araoka, T.; Okita, K.; Hotta, A.; Yamagata, K.; Osafune, K. A novel ADPKD model using kidney organoids derived from disease-specific human iPSCs. Biochem. Biophys. Res. Commun. 2020, 529, 1186–1194. [Google Scholar] [CrossRef]
  179. Kuraoka, S.; Tanigawa, S.; Taguchi, A.; Hotta, A.; Nakazato, H.; Osafune, K.; Kobayashi, A.; Nishinakamura, R. PKD1-Dependent Renal Cystogenesis in Human Induced Pluripotent Stem Cell-Derived Ureteric Bud/Collecting Duct Organoids. J. Am. Soc. Nephrol. 2020, 31, 2355–2371. [Google Scholar] [CrossRef]
  180. Bovo, E.; Huke, S.; Blatter, L.A.; Zima, A.V. The effect of PKA-mediated phosphorylation of ryanodine receptor on SR Ca2+ leak in ventricular myocytes. J. Mol. Cell Cardiol. 2017, 104, 9–16. [Google Scholar] [CrossRef]
Cells 13 01722 g001
Figure 1. PKD2 is conserved across diverse species and participates in organ development. (A) Phylogenetic tree of PKD2 across diverse species. PKD2 homologs were obtained from NCBI. The Accession Numbers are RDD46437, XP_030835833, XP_020911675, NP_609561, XP_052762183, XP_051064762, NP_502838, XP_043917296, XP_006007388, XP_041048068, NP_001002310, NP_001129990, XP_004911138, XP_034627128, XP_019343674, XP_063165668, NP_001026311, NP_000288, NP_001178863, NP_032887 and XP_028704444. The neighbor—joining phylogenetic trees were constructed using MEGA X with default parameters and bootstrapping with 10,000 replications was conducted to evaluate the phylogenetic tree. The conserved domain was annotated using CDD Tools. (B) PKD2 is involved in establishing left–right organ asymmetry, maintaining renal homeostasis, cardiovascular development, and signal transduction in reproduction and mating. (C) Schematic diagram of the human PKD2 structure.
Figure 1. PKD2 is conserved across diverse species and participates in organ development. (A) Phylogenetic tree of PKD2 across diverse species. PKD2 homologs were obtained from NCBI. The Accession Numbers are RDD46437, XP_030835833, XP_020911675, NP_609561, XP_052762183, XP_051064762, NP_502838, XP_043917296, XP_006007388, XP_041048068, NP_001002310, NP_001129990, XP_004911138, XP_034627128, XP_019343674, XP_063165668, NP_001026311, NP_000288, NP_001178863, NP_032887 and XP_028704444. The neighbor—joining phylogenetic trees were constructed using MEGA X with default parameters and bootstrapping with 10,000 replications was conducted to evaluate the phylogenetic tree. The conserved domain was annotated using CDD Tools. (B) PKD2 is involved in establishing left–right organ asymmetry, maintaining renal homeostasis, cardiovascular development, and signal transduction in reproduction and mating. (C) Schematic diagram of the human PKD2 structure.
Cells 13 01722 g001
Cells 13 01722 g002
Figure 2. PKD2 is involved in establishing left–right asymmetry. (A) Mechanism of PKD2 in left–right asymmetry of zebrafish. At the bud stage, immotile cilia in the left–right organizer (Kupffer’s vesicle, KV) maintain bilateral symmetry (top panel). At the 1 to 4 somite stage, motile cilia in KV generate a leftward flow (orange), which triggers the PKD2-dependent ciliary calcium oscillation on the left side of KV (bottom panel). Calcium oscillation inhibits dand5 expression and activates Nodal signaling in left-side cells, which further induces expression of Lefty2 and Pitx2 in the left side of KV. (B) General molecular mechanism of PKD2 in establishing left–right asymmetry. Motile cilia in the LRO (left–right organizer) generate leftward fluid flow. Immotile cilia detect mechanical signals via PKD2 and convert them into intracellular calcium signals. Intracellular calcium signals inhibit dand5 expression, which activates Nodal signaling. Consequently, Lefty2 and Pitx2 are expressed on the left side of LRO, promoting molecular processes of organ development in left–right asymmetric pattern.
Figure 2. PKD2 is involved in establishing left–right asymmetry. (A) Mechanism of PKD2 in left–right asymmetry of zebrafish. At the bud stage, immotile cilia in the left–right organizer (Kupffer’s vesicle, KV) maintain bilateral symmetry (top panel). At the 1 to 4 somite stage, motile cilia in KV generate a leftward flow (orange), which triggers the PKD2-dependent ciliary calcium oscillation on the left side of KV (bottom panel). Calcium oscillation inhibits dand5 expression and activates Nodal signaling in left-side cells, which further induces expression of Lefty2 and Pitx2 in the left side of KV. (B) General molecular mechanism of PKD2 in establishing left–right asymmetry. Motile cilia in the LRO (left–right organizer) generate leftward fluid flow. Immotile cilia detect mechanical signals via PKD2 and convert them into intracellular calcium signals. Intracellular calcium signals inhibit dand5 expression, which activates Nodal signaling. Consequently, Lefty2 and Pitx2 are expressed on the left side of LRO, promoting molecular processes of organ development in left–right asymmetric pattern.
Cells 13 01722 g002
Cells 13 01722 g003
Figure 3. Dysfunction of PKD2 results in polycystic kidney. (A) PKD2 plays a key role in maintaining intracellular calcium homeostasis under normal physiological conditions (left). PKD2 dysfunction disrupts this balance, leading to polycystic kidney disease (right). (B) Three key mechanisms are involved in polycystic kidney development due to PKD2 dysfunction: (1) PKD2 dysfunction reduces intracellular calcium, increasing cAMP levels, which enhances protein kinase A (PKA) activity [77,78,79,80,81]. PKA promotes cell proliferation via HEXIM1 inactivation and CREB/B-Raf/MEK/ERK signaling pathways [82,83,84,85]. (2) Reduced PKD2 phosphorylation causes ID2 retention in the nucleus, leading to E2F transcription factor activation and subsequent cell proliferation. ID2 also represses P21 expression, further enhancing E2F release [86,87,88]. (3) Increased mitofusin 2 (MFN2) expression enhances mitochondrial calcium uptake and respiration, promoting cell proliferation [89]. Studies on PKD1 indicate increased respiration inhibits AMPK, reduces TSC2 phosphorylation, and activates mTORC1, further driving cell proliferation [90,91].
Figure 3. Dysfunction of PKD2 results in polycystic kidney. (A) PKD2 plays a key role in maintaining intracellular calcium homeostasis under normal physiological conditions (left). PKD2 dysfunction disrupts this balance, leading to polycystic kidney disease (right). (B) Three key mechanisms are involved in polycystic kidney development due to PKD2 dysfunction: (1) PKD2 dysfunction reduces intracellular calcium, increasing cAMP levels, which enhances protein kinase A (PKA) activity [77,78,79,80,81]. PKA promotes cell proliferation via HEXIM1 inactivation and CREB/B-Raf/MEK/ERK signaling pathways [82,83,84,85]. (2) Reduced PKD2 phosphorylation causes ID2 retention in the nucleus, leading to E2F transcription factor activation and subsequent cell proliferation. ID2 also represses P21 expression, further enhancing E2F release [86,87,88]. (3) Increased mitofusin 2 (MFN2) expression enhances mitochondrial calcium uptake and respiration, promoting cell proliferation [89]. Studies on PKD1 indicate increased respiration inhibits AMPK, reduces TSC2 phosphorylation, and activates mTORC1, further driving cell proliferation [90,91].
Cells 13 01722 g003
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Wang, S.; Kang, Y.; Xie, H. PKD2: An Important Membrane Protein in Organ Development. Cells 2024, 13, 1722. https://doi.org/10.3390/cells13201722

AMA Style

Wang S, Kang Y, Xie H. PKD2: An Important Membrane Protein in Organ Development. Cells. 2024; 13(20):1722. https://doi.org/10.3390/cells13201722

Chicago/Turabian Style

Wang, Shuo, Yunsi Kang, and Haibo Xie. 2024. "PKD2: An Important Membrane Protein in Organ Development" Cells 13, no. 20: 1722. https://doi.org/10.3390/cells13201722

APA Style

Wang, S., Kang, Y., & Xie, H. (2024). PKD2: An Important Membrane Protein in Organ Development. Cells, 13(20), 1722. https://doi.org/10.3390/cells13201722

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop