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

J Mol Cell Biol. 2016 Dec;8(6):464-476. doi: 10.1093/jmcb/mjw022. Epub 2016 May 4.

Abstract

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), GSK3β expression is increased and plays a pathophysiological role. The current studies aimed to determine the mechanism for the increased GSK3β expression in PKD and its significance to disease progression. In mouse models of PKD, increases in renal GSK3β corresponded with increases in renal cAMP levels and disease progression. In vivo and in vitro studies revealed that GSK3β is a cAMP-responsive gene, and elevated cAMP levels, as seen in PKD, can increase GSK3β expression. In normal mice, vasopressin signaling induced by water deprivation increased GSK3β expression, which decreased following rehydration. Examination of the GSK3β promoter revealed five potential binding sites for the transcription factor, cAMP response element binding protein (CREB). CREB was found to bind to GSK3β promoter and essential for cAMP-mediated regulation of GSK3β. Importantly, this regulation was demonstrated to be part of a feed-forward loop in which cAMP through CREB regulates GSK3β expression, and GSK3β in turn positively regulates cAMP generation. GSK3β 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.

Keywords: CREB; GSK3β; PKD; PKD1-knockout; cAMP; in vitro cystogenesis; vasopressin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Body Fluids / metabolism
  • Cyclic AMP
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Dogs
  • Gene Knockout Techniques
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Humans
  • Kidney / enzymology
  • Kidney / pathology
  • Madin Darby Canine Kidney Cells
  • Mice, Inbred C57BL
  • Polycystic Kidney Diseases / metabolism*
  • Polycystic Kidney Diseases / pathology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction
  • TRPP Cation Channels
  • Vasopressins / metabolism

Substances

  • Cyclic AMP Response Element-Binding Protein
  • RNA, Messenger
  • TRPP Cation Channels
  • polycystic kidney disease 1 protein
  • Vasopressins
  • Cyclic AMP
  • Glycogen Synthase Kinase 3 beta