A cAMP and CREB-mediated feed-forward mechanism regulates GSK3? in polycystic kidney disease.

ABSTRACT: Glycogen synthase kinase 3? (GSK3?), 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), GSK3? expression is increased and plays a pathophysiological role. The current studies aimed to determine the mechanism for the increased GSK3? expression in PKD and its significance to disease progression. In mouse models of PKD, increases in renal GSK3? corresponded with increases in renal cAMP levels and disease progression. In vivo and in vitro studies revealed that GSK3? is a cAMP-responsive gene, and elevated cAMP levels, as seen in PKD, can increase GSK3? expression. In normal mice, vasopressin signaling induced by water deprivation increased GSK3? expression, which decreased following rehydration. Examination of the GSK3? promoter revealed five potential binding sites for the transcription factor, cAMP response element binding protein (CREB). CREB was found to bind to GSK3? promoter and essential for cAMP-mediated regulation of GSK3?. Importantly, this regulation was demonstrated to be part of a feed-forward loop in which cAMP through CREB regulates GSK3? expression, and GSK3? in turn positively regulates cAMP generation. GSK3? or 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.

SUBMITTER: Kakade VR 

PROVIDER: S-EPMC5181316 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature