Targeting TRPM3 As a Potential Therapeutic Approach for Autosomal Dominant Polycystic Kidney Disease

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 for 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.