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Genetic variants in Arhgef11 promote kidney injury and reduced renal function in Dahl S rats
Author(s) -
Jia Zhen,
Guo Zibiao,
Johnson Ashley C,
Garrett Michael R
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.955.10
Subject(s) - gene knockdown , rhoa , kidney , downregulation and upregulation , fasudil , small hairpin rna , vimentin , biology , microbiology and biotechnology , western blot , medicine , chemistry , endocrinology , cell culture , gene , signal transduction , genetics , immunology , immunohistochemistry , rho associated protein kinase
Through positional cloning, genetic variants in Arhgef11 , a Rho guanine nucleotide exchange factor, were implicated in kidney injury exhibited by the Dahl salt‐sensitive (S) rat. Kidney injury was associated with increased expression of Arhgef11 and upregulation of Rho‐ROCK pathway. To understand the mechanism by which altered expression and/or protein differences in ARHGEF11 could play a role in kidney injury, stably transduced Arhgef11 knockdown cell lines (lentiviral shRNA) as well as primary cultures of proximal tubule cells (PTC) were studied. Genetic knockdown of Arhgef11 resulted in reduced RhoA activity, decreased activation of Rho‐ROCK pathway (western blot) and less stress fiber formation versus control, similar to what was observed by pharmacological inhibition (fasudil). PTCs from S rats exhibited increased expression of Arhgef11 , activation of Rho‐ROCK, and decreased uptake of FITC‐albumin compared to control (minimal congenic). S primary PTCs stimulated with TGFβ1 were more prone (versus control) to epithelial‐mesenchymal transition (EMT) as demonstrated by increased expression of N‐Cadherin, Vimentin, Col1a1 and spindle shape morphology. In summary, these studies suggest that the functional significance of genetic variants in Arhgef11 may be of major importance in kidney injury in the S rat by promoting changes in cell morphology (Rho‐ROCK and/or EMT) and function of tubule cells.