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Targeting TRPM3 as a potential therapeutic approach for autosomal dominant polycystic kidney disease
1Deanery of Biomedical Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh, UK.
Abstract:
Cystic diseases, especially autosomal dominant polycystic kidney disease (ADPKD; incidence approx. 1/1000), are a leading cause of renal failure, caused by appearance and growth of renal cysts that can lead to renal failure in middle age. Most ADPKD cases are caused by mutations in PKD1 or PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2). PC1 is a mechanosensor that controls PC2, a Ca2+-permeable cation channel that, by regulating cytoplasmic Ca2+, prevents adenylyl cyclase producing cyst-promoting concentrations of cAMP. In other systems, there is evidence that PC2 interacts with TRPM3. We therefore examined the effect of pharmacological activators and inhibitors of TRPM3 on cyst formation in cultured mouse kidney rudiments exposed to a range of concentrations of forskolin, a cAMP-elevating drug commonly used experimentally to induce cysts in cultured kidneys. We found that TRPM3 inhibitors (isosakuranetin, primidone, diclofenac) increased cyst formation, while TRPM3 activators (CIM0216 and nifedipine) greatly reduced cyst formation and reduced the sensitivity of kidneys to forskolin. These preclinical, in-vitro data suggest that TRPM3 may be a promising target in ADPKD management.
Insights
Targeting the TRPM3 channel may offer a new approach for managing autosomal dominant polycystic kidney disease (ADPKD). Activating TRPM3 reduced cyst formation in preclinical kidney models, suggesting its therapeutic potential.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder leading to kidney failure.
- Mutations in PKD1 or PKD2 genes, encoding polycystin-1 (PC1) and polycystin-2 (PC2), cause ADPKD.
- PC2, a calcium channel regulated by PC1, influences intracellular calcium and cyclic AMP (cAMP) levels, impacting cystogenesis.
Purpose of the Study:
- To investigate the role of the TRPM3 channel in ADPKD cyst formation.
- To evaluate the effects of TRPM3 pharmacological modulators on cyst development in a preclinical kidney model.
Main Methods:
- Cultured mouse kidney rudiments were exposed to forskolin to induce cyst formation.
- The effects of TRPM3 activators (CIM0216, nifedipine) and inhibitors (isosakuranetin, primidone, diclofenac) were assessed.
- Changes in cyst formation and sensitivity to forskolin were quantified.
Main Results:
- TRPM3 inhibitors significantly increased cyst formation in cultured kidneys.
- TRPM3 activators markedly reduced cyst formation and decreased kidney sensitivity to forskolin.
- These findings highlight a functional interaction between TRPM3 and the cAMP pathway in kidney cyst development.
Conclusions:
- TRPM3 channel activity plays a critical role in regulating kidney cyst formation.
- Pharmacological activation of TRPM3 demonstrates potential for inhibiting ADPKD cystogenesis.
- TRPM3 represents a promising therapeutic target for managing ADPKD.
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