Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts

Sheng Xia, Xiaogang Li, Teri Johnson, Chris Seidel, Darren P. Wallace, Rong Li

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Polycystin 1 and polycystin 2 are large transmembrane proteins, which, when mutated, cause autosomal dominant polycystic kidney disease (ADPKD), a highly prevalent human genetic disease. The polycystins are thought to form a receptor-calcium channel complex in the plasma membrane of renal epithelial cells and elicit a calcium influx in response to mechanical stimulation, such as fluid flow across the apical surface of renal epithelial cells. The functional role of the polycystins in mechanosensation remains largely unknown. Here, we found that myocyte enhancer factor 2C (MEF2C) and histone deacetylase 5 (HDAC5), two key regulators of cardiac hypertrophy, are targets of polycystin-dependent fluid stress sensing in renal epithelial cells in mice. We show that fluid flow stimulation of polarized epithelial monolayers induced phosphorylation and nuclear export of HDAC5, which are crucial events in the activation of MEF2C-based transcription. Kidney-specific knockout of Mef2c, or genetrap-inactivation of a MEF2C transcriptional target, MIM, resulted in extensive renal tubule dilation and cysts, whereas Hdac5 heterozygosity or treatment with TSA, an HDAC inhibitor, reduced cyst formation in Pkd2 -/- mouse embryos. These findings suggest a common signaling motif between myocardial hypertrophy and maintenance of renal epithelial architecture, and a potential therapeutic approach to treat ADPKD.

Original languageEnglish (US)
Pages (from-to)1075-1084
Number of pages10
JournalDevelopment
Volume137
Issue number7
DOIs
StatePublished - Apr 1 2010

Keywords

  • Autosomal dominant polycystic kidney disease
  • Histone deacetylase 5
  • Mouse
  • Myocyte enhancer factor 2C

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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