Search Results (290)

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a systemic ciliopathy resulting from loss-of-function mutations in the PKD1 and PKD2 genes, which encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC1 and PC2 regulate mechanosensation, calcium signaling, and key pathways controlling tubular epithelial structure and function. Loss of PC1/PC2 disrupts calcium homeostasis, elevates cAMP, and activates proliferative cascades such as PKA–B-Raf–MEK–ERK, mTOR, and Wnt, driving cystogenesis via epithelial proliferation, impaired apoptosis, fluid secretion, and fibrosis. Recent evidence also implicates novel signaling axes in ADPKD progression including, the Hippo pathway, where dysregulated YAP/TAZ activity enhances c-Myc-mediated proliferation; the stimulator of interferon genes (STING) pathway, which is activated by mitochondrial DNA release and linked to NF-κB-driven inflammation and fibrosis; and the TWEAK/Fn14 pathway, which mediates pro-inflammatory and pro-apoptotic responses via ERK and NF-κB activation in tubular cells. Mitochondrial dysfunction, oxidative stress, and maladaptive extracellular matrix remodeling further exacerbate disease progression. A refined understanding of ADPKD’s complex signaling networks provides a foundation for precision medicine and next-generation therapeutics. This review gathers recent molecular insights and highlights both established and emerging targets to guide targeted treatment strategies in ADPKD. Full article

Renal function refers to the combined actions of the glomerulus and tubular system to achieve homeostasis in bodily fluids. While the glomerulus is essential in the first step of urine formation through a coordinated filtration mechanism, the tubular system carries out active mechanisms of secretion and reabsorption of solutes and proteins using specific transporters in the epithelial cells. The assessment of renal function usually focuses on glomerular function, so the tubular function is often underestimated as a fundamental part of daily clinical practice. Therefore, it is essential to properly understand the tubular physiological mechanisms and their clinical association with prevalent human pathologies. This review discusses the primary solutes handled by the kidneys, including glucose, amino acids, sodium, potassium, calcium, phosphate, citrate, magnesium and uric acid. Additionally, it emphasizes the significance of physicochemical characteristics of urine, such as pH and osmolarity. The use of a concise methodology for the comprehensive assessment of urine should be strengthened in the basic training of nephrologists when dealing with problems such as water and electrolyte balance disorders, acid-base disorders, and harmful effects of commonly used drugs such as chemotherapy, antibiotics, or diuretics to avoid isolated replacement of the solute without carrying out comprehensive approaches, which can lead to potentially severe complications. Full article

Cisplatin (Cis) is a widely used chemotherapy drug, but its nephrotoxicity limits its clinical application. Acute kidney injury (AKI) is a common complication, restricting long-term use. This study investigates the mechanisms of cisplatin-induced AKI and explores potential therapeutic targets. C57BL/6J mice were intraperitoneally injected with 20 mg/kg cisplatin to establish an AKI model. Serum creatinine, urea nitrogen, and tubular injury biomarkers (NGAL, KIM-1) progressively increased, indicating kidney dysfunction. Mitochondrial ATP levels significantly decreased, along with reduced mitochondrial fission and fusion, suggesting mitochondrial dysfunction. Increased oxidases and reduced antioxidants indicated redox imbalance, and metabolic reprogramming was observed, with lipid deposition, impaired fatty acid oxidation (FAO), and enhanced glycolysis in proximal tubular epithelial cells (PTECs). Nuclear factor erythroid 2-related factor 2 (NRF2) is a key transcriptional regulator of redox homeostasis and mitochondrial function. We found NRF2 levels increased early in AKI, followed by a decrease in vivo and in vitro, suggesting activation in the stress response. Nfe2l2 knockout mice showed aggravated kidney injury, characterized by worsened kidney function and histopathological damage. Mechanistically, Nfe2l2 knockout resulted in redox imbalance, reduced ATP synthesis, mitochondrial dysfunction and metabolic dysregulation. Furthermore, we activated NRF2 using dimethyl fumarate (DMF), observing a reduction in kidney damage and lipid deposition in mice. In conclusion, activating NRF2-dependent antioxidant pathways plays a crucial role in protecting against cisplatin-induced AKI. NRF2 may serve as a potential target for developing therapeutic strategies to prevent cisplatin nephrotoxicity. Full article

Oxidative stress plays a crucial role in disease pathogenesis. While reactive oxygen species (ROS) directly cause cellular injury, emerging evidence suggests oxidatively modified proteins like albumin may also contribute significantly to tissue damage. Although oxidized albumin (ox-Alb) is linked to renal pathology, the direct effects and mechanisms of ox-Alb on renal cell injury remain unclear. This study was created to address these questions. In mouse models of renal injury initiated by vitamin C/copper or ischemia/reperfusion, levels of serum ox-Alb were significantly elevated. The treatment of albumin with copper/vitamin C increased Alb carbonylation and reduced the number of sulfhydryl groups, causing Alb oxidation. In cultured renal tubular epithelial NRK-52E cells, ox-Alb triggered cell death, associated with increased intracellular albumin accumulation—enhanced cellular protein carbonylation, and p38 MAPK activation. Notably, ox-Alb induced ferroptosis, evidenced by decreased GPX4 and xCT, increased ACSL4, elevated iron and lipid peroxidation, and suppression by deferoxamine and liproxstatin-1. In vivo, administration of ox-Alb exacerbated doxorubicin-induced nephropathy, as indicated by the elevated BUN, creatinine, and proteinuria, and intensified renal ferroptotic responses, including altered GPX4 and ACSL4. Our findings demonstrate that ox-Alb induces renal cell ferroptosis and promotes renal disease progression, suggesting its pivotal pathogenic role in oxidative stress-related kidney diseases. Full article

Polyomaviruses have the potential to cause significant morbidity not only in transplant medicine, but also in other forms of disease or variants of immunosuppression. In kidney transplant recipients or recipients of human stem cell transplants, the BK-Virus is the major proponent of manifestations such as BKPyV-associated nephropathy or hemorrhagic cystitis. As no polyomavirus-specific drug with proven in vivo effects has been developed so far, methods to screen for such drugs are important. This work describes the establishment of a virus-secreting cell line. By infecting a pre-established monkey kidney cell line (COS-1) with a non-rearranged human BK polyomavirus isolated from a kidney transplant patient suffering from BKPyV-associated nephropathy, a continuously replicating cell type with consistent virus secretion could be established and was termed COSSA. Measurements of BKPyV replication, virion production, and secretion were performed both intracellularly and in the cell supernatant. Viral proteins such as VP1 and LTAg were accurately tracked by confocal microscopy, as well as by immunoblot and qPCR. An intracellular flow cytometry (FACS) assay detecting VP1 protein was established and revealed an expanded range of positive intracellular signals. The viruses produced proved to be infectious in human tubular epithelial cell lines. Long-range sequencing of the COSSA genome using Oxford Nanopore Technology revealed a total of five distinct BKPyV integration events. One integration of a partial BKPyV genome was located upstream of the epidermal growth factor receptor gene. The second and third, both truncated forms of integration, were close to histocompatibility gene locuses, while the fourth was characterized by a ninefold and the fifth by a fourfold tandem repeat of the BKPyV genome. From both of the repeat forms, virus replicates were derived showing deletions/duplications on early and late genes and inversions within the non-coding control region (NCCR). This pattern of repetitive viral genome integration is a potential key driver of enhanced viral replication and increased virion assembly, ultimately supporting efficient virus egress. Quantitative PCR analysis confirmed the release of approximately 10⁸/mL viral units per 48 h from 2 × 10⁵ COSSA cells into the culture supernatant. Notably, the NCCR region of the most frequent copies of circular virus and the integrated tetrameric tandem repeat exhibited a rearranged configuration, which may contribute to the observed high replication dynamics. The establishment of a consistent methodology to generate and secrete BKPyV from a cell line is expected to significantly facilitate antiviral drug development. Full article

Studies on populations exposed to inorganic arsenic (iAs) have shown an association with the development of chronic kidney disease (CKD) and renal cell carcinoma (RCC). However, there are few studies addressing how acute exposure of the human kidney to iAs might lead to the long-term alterations that might lead to CKD or RCC. This laboratory’s hypothesis is that renal exposure to iAs might alter the renal cells responsible for the repair and regeneration of nephrons damaged by iAs exposure or other renal toxicants. The kidney possesses a minority epithelial cell population that co-expresses PROM1 and CD24, which are believed to be involved in renal epithelial cell repair. The purpose of this work is to understand the pathogenesis of CKD in renal cortical epithelial cells. Our model consists of acute and chronic exposure of i-As (III) to “Human Renal Tubular Precursor TERT” (HRTPT). The microarray and gene validation study demonstrated a sudden induction of microfibril associated protein 5 (MFAP5) and carcinoembryonic antigen related cell adhesion molecule 5 and 6 (CEACAM 5 and 6) in chronic i-As (III)-exposed cells. Chronically exposed cells also exhibited an induction of the pAKT/AKT pathway and SOX9 transcription factor. The targeting of MFAP5 and CEACAM 5/6 could, therefore, provide a potential therapeutic approach to CKD. Full article

Diabetic kidney disease (DKD), a well-characterized microvascular complication associated with the progression of diabetes mellitus, has been identified as the leading etiological factor contributing to the global burden of end-stage kidney disease (ESKD). Historically, DKD research has predominantly centered on glomerular mechanisms; however, recent studies have increasingly emphasized the critical role of tubular dysfunction. Extensive evidence has elucidated the key pathological drivers of tubular injury in DKD, encompassing metabolic dysregulation, pro-inflammatory signaling pathways, diverse cellular stress responses, and epithelial–mesenchymal transition (EMT). Furthermore, emerging mechanistic studies reveal that autophagic flux impairment and epigenetic memory formation collaboratively drive cellular senescence in DKD. Regarding the treatment of DKD, various hypoglycemic drugs, as well as hypotensive drugs, and microcirculatory improvers have garnered significant attention. Recently, stem cell-based interventions and precision gene editing techniques have unveiled novel therapeutic paradigms for DKD, fundamentally expanding the treatment arsenal beyond conventional pharmacotherapy. This review synthesizes updated insights into the pathogenesis of tubular injury in DKD and highlights promising therapeutic strategies for managing this condition. Full article

Cisplatin (CIS) is a widely used chemotherapeutic agent that is highly effective against various cancers. However, its clinical application is frequently limited by its substantial nephrotoxic side effects. The gastrin-releasing peptide receptor (GRPR), a critical regulator in inflammatory diseases, has been identified as a promising therapeutic target. Our previous studies have demonstrated that the GRPR antagonists PD176252 and RH-1402 can mitigate CIS-induced nephrotoxicity through anti-inflammatory mechanisms. Based on these findings, we designed and synthesized a series of 2-arylpropanoic acid-L-tryptophan derivatives to enhance the therapeutic effects. Among these compounds, 3m exhibited superior renal protection by significantly improving mouse renal tubular epithelial cell (mRTEC) viability from 50.2 ± 2.6% to 80.5 ± 3.9%, surpassing PD176252 (70.8 ± 1.4%) and RH-1402 (73.9 ± 3.7%). Moreover, compound 3m markedly reduced the expression of kidney injury molecule-1 (KIM-1) and inflammatory cytokines [Tumor Necrosis Factor-α (TNF-α), Interleukin-6 (IL-6), Monocyte Chemoattractant Protein-1 (MCP-1)]. Finally, molecular docking results revealed that 3m exhibited a high binding affinity for GRPR. Computational predictions using SwissADME further indicated that 3m possesses favorable drug-like properties, thereby supporting its potential as a promising candidate for mitigating CIS-induced nephrotoxicity. Full article

Acute kidney injury (AKI) causes damage to the renal epithelium, initiating a reparative process intended to restore renal function. Although effective repair can result in the complete recovery of kidney function, this process is frequently incomplete. In instances where repair is unsuccessful, the kidney experiences maladaptive alterations that may progressively result in chronic kidney disease (CKD), a phenomenon referred to as failed repair. This condition is precipitated by hypotensive, septic, or toxic insults, which initiate a series of pathophysiological processes, including microcirculatory dysfunction, the activation of inflammatory responses, and the death of tubular epithelial cells. These events collectively compromise renal function and trigger a complex repair response. This review provides a comprehensive examination of the multifactorial mechanisms underlying the initiation and progression of AKI, the regenerative pathways facilitating structural recovery in severely damaged kidneys, and the critical transition from adaptive repair to maladaptive remodeling. Central to this transition are mechanisms such as epigenetic reprogramming, G2/M cell-cycle arrest, cellular senescence, mitochondrial dysfunction, metabolism reprogramming, and cell death, which collectively drive the progression of CKD. These mechanistic insights offer a robust foundation for the development of targeted therapeutic strategies aimed at enhancing adaptive renal repair. Full article

This study investigated the protective effects of corynoxeine, a natural alkaline compound, on colistin-caused nephrotoxicity using a murine model. Forty mice were divided randomly into control, corynoxeine-only (20 mg/kg/day, intraperitoneal injection), colistin-only (20 mg/kg/day, intraperitoneal injection), and colistin (20 mg/kg/day) + corynoxeine (5 and 20 mg/kg/day) groups (8 mice in each group). All treatments were maintained for seven consecutive days. Results showed that colistin treatment at 20 mg/kg/day for seven days significantly increased serum urea nitrogen and creatinine levels and induced the loss and degeneration of renal tubular epithelial cells, which were markedly ameliorated by corynoxeine co-treatment at 5 or 20 mg/kg/day. Corynoxeine supplementation also markedly attenuated colistin-induced increases in malondialdehyde levels and decreases in reduced glutathione levels and superoxide dismutase and catalase activities in the kidneys. Furthermore, corynoxeine supplementation significantly decreased the expression of transforming growth factor β (TGF-β) and nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4 (NOX4) proteins and nuclear factor kappa B (NF-κB), interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-α mRNAs, while it significantly increased the expression of erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) proteins in the kidneys. In conclusion, these results reveal that corynoxeine can protect against colistin-induced nephrotoxicity in mice by inhibiting oxidative stress and inflammation, which may partly be attributed to its ability on the activation of the Nrf2/HO-1 pathway and the inhibition of the TGF-β/NOX4 and NF-κB pathways. Full article

Cellular communication network factor 2 (CCN2, also known as CTGF) is a complex protein that regulates numerous cellular functions. This biomolecule exhibits dual functions, depending on the context, and can act as a matricellular protein or as a growth factor. CCN2 is an established marker of fibrosis and a well-known mediator of kidney damage, involved in the regulation of inflammation, extracellular matrix remodeling, cell death, and activation of tubular epithelial cell (TECs) senescence. In response to kidney damage, cellular senescence mechanisms are activated, linked to regeneration failure and progression to fibrosis. Our preclinical studies using a total conditional CCN2 knockout mouse demonstrate that CCN2 plays a significant role in the development of a senescence phenotype after exposure to a nephrotoxic agent. CCN2 induces cell growth arrest in TECs, both in the early phase and in the chronic phase of folic acid nephropathy (FAN), associated with cell-death/necroinflammation and fibrosis, respectively. Renal CCN2 overexpression was found to be linked to excessive collagen accumulation in tubulointerstitial areas, microvascular rarefaction, and a decline in renal function, which were observed three weeks following the initial injury. All these findings were markedly diminished in conditional CCN2 knockout mice. In the FAN model, injured senescent TECs are associated with microvascular rarefaction, and both were modulated by CCN2. In primary cultured endothelial cells, as previously described in TECs, CCN2 directly induced senescence. The findings collectively demonstrate the complexity of CCN2, highlight the pivotal role of cellular senescence as an important mechanism in renal injury, and underscore the critical function of this biomolecule in kidney damage progression. Full article

Background/Objectives: The human kallikrein-related peptidase 6 (KLK6), a serine protease with trypsin-like properties, belongs to the 15-member kallikrein (KLK) gene family and is predominantly recognized for its role in oncogenesis, neurodegenerative disorders, and skin conditions. Aquaporins (AQPs) are integral membrane proteins that facilitate water transport across cell membranes. AQP1 is constitutively active in the kidneys and plays a crucial role in reabsorbing filtered water, while AQP2 is regulated by vasopressin and is essential for maintaining body fluid homeostasis. The primary objective of the present study is to investigate the spatio-temporal expression patterns of KLK6, AQP1, and AQP2 throughout normal human nephrogenesis and congenital kidney and urinary tract (CAKUT) abnormalities: duplex kidneys, horseshoe kidneys, and dysplastic kidneys. Methods: An immunofluorescence analysis of KLK6, AQP1, and AQP2 was performed on 37 paraffin-embedded fetal kidney samples. The area percentage of KLK6 in the kidney cortex was calculated in normal developing samples during developmental phases 2, 3, and 4 and compared with CAKUT samples. Results: KLK6 exhibits distinct spatiotemporal expression patterns during human kidney development, with consistent localization in proximal tubules. Its subcellular positioning shifts from the basolateral cytoplasm in early phases to the apical cytoplasm in later stages, which may be strategically positioned to act on its substrate in either the peritubular space or the tubular fluid. KLK6 expression followed a quadratic trajectory, peaking at Ph4. This marked increase in the final developmental phase aligns with its strong expression in mature kidneys, suggesting a potential role in proximal tubule differentiation and functional maturation through facilitating extracellular matrix remodeling and activating proteinase-activated receptors, modulating the signaling pathways that are essential for tubular development. In duplex kidneys, structural abnormalities such as ureteral obstruction and hydronephrosis may upregulate KLK6 as part of a reparative response, while its downregulation could impair epithelial remodeling and cytoskeletal integrity, exacerbating dysplastic phenotypes. Conclusions: These findings highlight the potential of KLK6 involvement in normal kidney development and the pathology of CAKUT. Full article

The renin–angiotensin system helps regulate the endocrine system in modulating blood pressure, fluid volume, and body fluid electrolyte levels. The disruption of the renin–angiotensin system can lead to kidney disease onset and progression. However, the mechanism by which kidney angiotensinogen expression and secretion induce the onset and progression of diabetic nephropathy remains unclear. In this study, we used renal proximal tubular epithelial cells, which express high levels of angiotensinogen, to examine food components that regulate angiotensinogen secretion. The renal proximal tubular epithelial cells were first treated with catalase (antioxidant), daidzein, equol (an isoflavone), a MAP kinase inhibitor, ERK, p38, or JNK and then stimulated with hydrogen peroxide. After 24 h, we collected a culture medium to perform an enzyme-linked immunosorbent assay test for angiotensinogen and cells in order to perform real-time PCR to detect angiotensinogen. We found that angiotensinogen secretion increased as the hydrogen peroxide concentration increased. Catalase, daidzein, and equol decreased angiotensinogen expression and secretion. To investigate the cell signaling mechanism involved in these effects, we assessed the contribution of the MAP kinase cascade. Our data suggest the contribution of p38 and JNK. Our study shows that, in proximal tubular epithelial cells, hydrogen peroxide stimulates angiotensinogen secretion. Isoflavones and p38 inhibited angiotensinogen secretion. Full article

Renal fibrosis is a critical pathological feature of various chronic kidney diseases, with hypoxia being recognized as an important factor in inducing fibrosis. Yaks have long inhabited high-altitude hypoxic environments and do not exhibit fibrotic damage under chronic hypoxia. However, the underlying protective mechanisms remain unclear. This study compared the renal tissue structure and collagen volume between low-altitude cattle and high-altitude yaks, revealing that yaks possess a significantly higher number of renal tubules than cattle, though collagen volume showed no significant difference. Under hypoxic treatment, we observed that chronic hypoxia induced renal fibrosis in cattle, but did not show a significant effect in yaks, suggesting that the hypoxia adaptation mechanisms in yaks may have an anti-fibrotic effect. Further investigation demonstrated a significant upregulation of P-AMPK/AMPK, Parkin, PINK1, LC3Ⅱ/Ⅰ, and BECN1, alongside a downregulation of P-mTOR/mTOR in yak kidneys. Additionally, hypoxia-induced renal tubular epithelial cells (RTECs) showed increased expression of mitophagy-related proteins, mitochondrial membrane depolarization, and an increased number of lysosomes, indicating that hypoxia induces mitophagy. By regulating the mitophagy pathway through drugs, we found that under chronic hypoxia, activation of mitophagy upregulated E-cadherin protein expression while downregulating the expression of Vimentin, α-SMA, Collagen I, and Fibronectin. Simultaneously, there was an increase in SLC7A11, GPX4, and GSH levels, and a decrease in ROS, MDA, and Fe²⁺ accumulation. Inhibition of mitophagy produced opposite effects on protein expression and cellular markers. Further studies identified ferroptosis as a key mechanism promoting renal fibrosis. Moreover, in renal fibrosis models, mitophagy reduced the accumulation of ROS, MDA, and Fe²⁺, thereby alleviating ferroptosis-induced renal fibrosis. These findings suggest that chronic hypoxia protects yaks from hypoxia-induced renal fibrosis by activating mitophagy to inhibit the ferroptosis pathway. Full article

The kidneys are integral to homeostasis but are susceptible to nephrotoxic compounds. Proximal tubular epithelial cells (PTECs) mediate drug metabolism and transport and are widely used in preclinical studies. However, commercial PTECs are limited in availability and physiological relevance. This study aimed to develop a novel, reliable protocol for isolating and culturing PTECs from human kidney biopsies. Primary PTECs were isolated from kidney biopsies of two patients (MFUM-RPTEC-1 and MFUM-RPTEC-2). Their morphology, population doubling time, transepithelial electrical resistance (TEER), and phenotypic markers were evaluated. Polarization and transporter expression were analyzed using cells cultured on Transwell inserts. Colonies formed within 24–48 h, with confluence reached by 8–10 days and dome (hemicyst) formation by day 13. TEER values peaked at 190 Ω/cm² after 7–14 days, confirming tight junction formation. Immunostaining identified characteristic markers (e.g., SGLT2, OAT1/3, OCT2, P-gp, MRP4, MATE1, N-cadherin, ZO-1, CK-18). Cells cultured on Transwell plates exhibited native polarization, expressing transporters crucial for drug excretion on apical and basolateral surfaces. We present two robust protocols for isolating and characterizing PTECs, offering a scalable method to obtain functional, polarized cells from scarce biopsy material. The isolated PTECs, therefore, present a valuable platform for preclinical studies, especially for drug excretion testing through the expressed transporters. Drug competition for these transporters during tubular secretion is also a common cause of nephrotoxicity. Full article