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

Vijayakumar R. Kakade, Shixin Tao, Madhumitha Rajagopal, Xia Zhou, Xiaogang Li, Alan S.L. Yu, James P. Calvet, Pankaj Pandey, Reena Rao

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)464-476
Number of pages13
JournalJournal of Molecular Cell Biology
Volume8
Issue number6
DOIs
StatePublished - Jan 1 2016
Externally publishedYes

Keywords

  • cAMP
  • CREB
  • GSK3β
  • In vitro cystogenesis
  • PKD
  • PKD1-knockout
  • Vasopressin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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  • Cite this

    Kakade, V. R., Tao, S., Rajagopal, M., Zhou, X., Li, X., Yu, A. S. L., Calvet, J. P., Pandey, P., & Rao, R. (2016). A cAMP and CREB-mediated feed-forward mechanism regulates GSK3β in polycystic kidney disease. Journal of Molecular Cell Biology, 8(6), 464-476. https://doi.org/10.1093/jmcb/mjw022