A cAMP and CREB-mediated feed-forward mechanism regulates GSK3β in polycystic kidney disease

Glycogen synthase kinase 3β(GSK3β),a serine/threonine protein kinase,is commonly known to be regulated at the level of its activity.However,in some diseases including polycystic kidney disease(PKD),GSK3βexpression is increased and plays a pathophysiological role.The current studies aimed to determine the mechanism for the increased GSK3βexpression in PKD and its significance to disease progression.In mouse models of PKD,increases in renal GSK3βcorresponded with increases in renal cAMP levels and disease progression.In vivo and in vitro studies revealed that GSK3βis a cAMP-responsive gene,and elevated cAMP levels,as seen in PKD,can increase GSK3βexpression.In normal mice,vasopressin signaling induced by water deprivation increased GSK3βexpression,which decreased following rehydration.Examination of the GSK3βpromoter revealed five potential binding sites for the transcription factor,cAMP response element binding protein(CREB).CREB was found to bind to GSK3βpromoter and essential for cAMP-mediated regulation of GSK3β.Importantly,this regulation was demonstrated to be part of a feedforward loop in which cAMP through CREB regulates GSK3βexpression,and GSK3βin turn positively regulates cAMP generation.GSK3βor CREB inhibition reduced transepithelial fluid secretion and cyst expansion in vitro.Thus,disruption at any point of this destructive cycle may be therapeutically useful to reduce cyst expansion and preserve renal function in PKD.