Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts.
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.
Xia
Sheng
S
The Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
Li
Xiaogang
X
Johnson
Teri
T
Seidel
Chris
C
Wallace
Darren P
DP
Li
Rong
R
D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007684:Kidney Tubules / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D064326:MEF2 Transcription Factors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012212:Rheology; D033081:Shear Strength; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism*
D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D050396:TRPP Cation Channels; C578041:Mef2c protein, mouse; C498618:Hdac5 protein, mouse