Ca2+ signalling in ADPKD: mechanisms and consequences.

Mutations in the genes encoding the polycystin-1 and -2 proteins lead to autosomal dominant polycystic kidney disease (ADPKD), the most common inherited renal disease. Hallmark of the disease is the progressive development of renal cysts that lead to kidney failure. The molecular mechanisms underlying the formation of cysts are of major interest to develop novel strategies for treatment and prevention of ADPKD.  Disturbed Ca2+ signaling in kidney epithelial cells from ADPKD patients is generally regarded as the prime event triggering cyst formation. These changes in Ca2+ signaling are believed to stimulate cAMP and mTOR activity, as well as alter the autophagy/apoptosis balance. However, the Ca2+ signaling toolbox is poorly characterized in ADPKD epithelial cells. Therefore, we propose a project that will characterize the Ca2+ signaling mechanisms in human proximal tubule and collecting duct epithelial cells and study how they are altered in cells from ADPKD donors. We aim to identify receptors and channels that mobilize Ca2+ in the plasma membrane and the primary cilium, and study downstream pathways such as cAMP metabolism, mTOR activity and autophagy/apoptosis. Finally, we will test the potential of these pathways to prevent or slow down cyst formation. We anticipate to provide new insights in the fundamental molecular mechanisms underlying ADPKD, which will be useful for the development of novel and innovative treatment strategies.