Ciliary G-Protein Coupled Receptor Signaling in Polycystic Kidney Disease
Abstract
1. Introduction
2. Primary Cilia and Their Role in Cellular Signaling
2.1. Ciliary GPCR Structure and Function
2.1.1. Physiological Roles of GPCRs
2.1.2. Role of GPCRs in Kidney Function
2.2. Mechanisms Linking Ciliary GPCR Dysfunction to PKD Pathogenesis
2.3. Mechanosensation and Fluid Flow Signaling in Ciliary GPCRs and PC1
3. Therapeutic Implications and Drug Development
4. Current Challenges and Future Directions
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ADPKD | Autosomal Dominant Polycystic Kidney Disease |
ADPKD1 | Autosomal Dominant Polycystic Kidney Disease Type 1 |
ADPKD2 | Autosomal Dominant Polycystic Kidney Disease Type 2 |
AT1R | Angiotensin II Type 1 Receptor |
BMP | Bone Morphogenetic Protein |
cAMP | Cyclic Adenosine Monophosphate |
CFTR | Cystic Fibrosis Transmembrane Conductance Regulator |
cGMP | Cyclic Guanosine Monophosphate |
CKD | chronic kidney disease |
COOH | Carboxy Terminus |
DR5 | Dopamine Receptor 5 |
eGFR | Estimated Glomerular Filtration Rate |
EP1–EP4 | Prostaglandin E2 Receptors 1 to 4 |
EP4 | Prostaglandin E2 receptor 4 |
FDA | Food and Drug Administration |
FFAR4 | Free fatty acid receptor 4 |
GAIN | GPCR-Autoproteolytic Inducing Domain |
GALR2 | Galanin receptor 2 |
GBD | G protein-binding domain |
GFR | Glomerular Filtration Rate |
GPCR | G-Protein Coupled Receptor |
GPS | GPCR Proteolysis Site |
Gs, Gi, Gq, G12 | G Protein Classes |
Gα, Gβ, Gγ | G Protein Subunits Alpha, Beta, Gamma |
HDAC5 | Histone Deacetylase 5 |
IC50 | Half Maximal Inhibitory Concentration |
MDRD | Modification of Diet in Renal Disease |
mGFR | measured Glomerular Filtration Rate |
mTOR | Mammalian Target of Rapamycin |
NDI | Nephrogenic Diabetes Insipidus |
PC1 | Polycystin-1 |
PC2 | Polycystin-2 |
PKA | Protein Kinase A |
PKD | Polycystic Kidney Disease |
Pkd1 | Polycystic Kidney Disease gene 1. |
Pkd2 | Polycystic Kidney Disease gene 2. |
PLC | Phospholipase C |
RAAS | Renin–Angiotensin–Aldosterone system |
RTK | Receptor Tyrosine Kinase |
SSRT2, SSRT3, SSRT5 | Somatostatin Receptor Subtypes 2, 3, and 5 |
SST | Somatostatin |
TGF-β | Transforming Growth Factor Beta |
TSC2 | Tuberin (Tuberous Sclerosis Complex 2) |
UT-A1 | Urea Transporter A1 |
UT-A3 | Urea Transporter A3 |
V2R | Vasopressin V2 Receptor |
WNT | Wingless-related integration site |
μm | Micrometer |
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Drug | Target and MOA | Pre-Clinical Outcome | Clinical Trial Outcome | References |
---|---|---|---|---|
OPC 31260 | V2R antagonist | ↓ Cyst ratio and kidney weight after 3 weeks high-dose | [78] | |
Tolvaptan | V2R antagonist | ↓ cAMP, ↓ proliferation, ↓ chloride secretion, ↓ cyst growth | ↓ Kidney volume growth (2.8% vs. 5.5% placebo), ↓ function decline | [80,81,82] |
RWJ-676070 | V1a and V2 receptor antagonists | ↓ BP and proteinuria, partial glomerular/tubular restoration | ↓ eGFR decline (p < 0.001) | [83] |
Octreotide | Somatostatin; SSRT2, 3, and 5 agonists | ↓ cAMP, ↓ liver/kidney cyst volume, ↓ mitotic index | ↓ Kidney growth and function loss in high-risk ADPKD patients | [88,91,92] |
Pasireotide | Somatostatin; SSRT2, 3, and 5 agonists | ↓ Hepatorenal cystogenesis in rodent models | - | [89] |
Tolvaptan and pasireotide -combination | V2R antagonist And SSRT2, 3, and 5 agonists | ↓ Cystic and fibrotic volume, normalized cAMP | - | [90] |
Fenoldopam | Dopamine- DR5 agonist | ↑ Cilia function via NO production in response to shear | - | [93] |
Levodopa | Non-specific dopamine agonist | - | ↓ BP in PKD patients with borderline hypertension | [93] |
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Buqaileh, R.; Alshriem, L.A.; AbouAlaiwi, W. Ciliary G-Protein Coupled Receptor Signaling in Polycystic Kidney Disease. Int. J. Mol. Sci. 2025, 26, 4971. https://doi.org/10.3390/ijms26114971
Buqaileh R, Alshriem LA, AbouAlaiwi W. Ciliary G-Protein Coupled Receptor Signaling in Polycystic Kidney Disease. International Journal of Molecular Sciences. 2025; 26(11):4971. https://doi.org/10.3390/ijms26114971
Chicago/Turabian StyleBuqaileh, Raghad, Lubna A. Alshriem, and Wissam AbouAlaiwi. 2025. "Ciliary G-Protein Coupled Receptor Signaling in Polycystic Kidney Disease" International Journal of Molecular Sciences 26, no. 11: 4971. https://doi.org/10.3390/ijms26114971
APA StyleBuqaileh, R., Alshriem, L. A., & AbouAlaiwi, W. (2025). Ciliary G-Protein Coupled Receptor Signaling in Polycystic Kidney Disease. International Journal of Molecular Sciences, 26(11), 4971. https://doi.org/10.3390/ijms26114971