Mechanoprotection by Polycystins against Apoptosis Is Mediated through the Opening of Stretch-Activated K2P Channels

SummaryHow renal epithelial cells respond to increased pressure and the link with kidney disease states remain poorly understood. Pkd1 knockout or expression of a PC2 pathogenic mutant, mimicking the autosomal dominant polycystic kidney disease, dramatically enhances mechanical stress-induced tubular apoptotic cell death. We show the presence of a stretch-activated K+ channel dependent on the TREK-2 K2P subunit in proximal convoluted tubule epithelial cells. Our findings further demonstrate that polycystins protect renal epithelial cells against apoptosis in response to mechanical stress, and this function is mediated through the opening of stretch-activated K2P channels. Thus, to our knowledge, we establish for the first time, both in vitro and in vivo, a functional relationship between mechanotransduction and mechanoprotection. We propose that this mechanism is at play in other important pathologies associated with apoptosis and in which pressure or flow stimulation is altered, including heart failure or atherosclerosis.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► Mechanical stress-induced renal tubular cell death is influenced by polycystins
► Polycystins condition the stretch sensitivity of SAKs/K2P channels
► Inhibition of SAK mechanogating by PC2 mutants involves the actin cytoskeleton
► SAK knockout enhances tubular cell death induced by mechanical stress