Gα12 Activation in Podocytes Leads to Cumulative Changes in Glomerular Collagen Expression, Proteinuria and Glomerulosclerosis

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Gα12 Activation in Podocytes Leads to Cumulative Changes in Glomerular Collagen Expression, Proteinuria and Glomerulosclerosis

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Title: Gα12 Activation in Podocytes Leads to Cumulative Changes in Glomerular Collagen Expression, Proteinuria and Glomerulosclerosis
Author: Boucher, Ilene; Yu, Wanfeng; Beaudry, Sarah; Negoro, Hideyuki; Tran, Mei; Pollak, Martin; Henderson, Joel; Denker, Bradley M.

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Citation: Boucher, Ilene, Wanfeng Yu, Sarah Beaudry, Hideyuki Negoro, Mei Tran, Martin Pollak, Joel Henderson, et al. 2012. Gα12 activation in podocytes leads to cumulative changes in glomerular collagen expression, proteinuria and glomerulosclerosis. Laboratory Investigation 92(5): 662-675.
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Abstract: Glomerulosclerosis is a common pathologic finding that often progresses to renal failure. The mechanisms of chronic kidney disease progression are not well-defined but may include activation of numerous vasoactive and inflammatory pathways. We hypothesized that podocytes are susceptible to filtered plasma components including hormones and growth factors that stimulate signaling pathways leading to glomerulosclerosis. Gα12 couples to numerous G-protein-coupled receptors (GPCR) and regulates multiple epithelial responses including proliferation, apoptosis, permeability and the actin cytoskeleton. Herein, we report that genetic activation of Gα12 in podocytes leads to time dependent increases in proteinuria and glomerulosclerosis. To mimic activation of Gα12-pathways, constitutively active Gα12(QL) was conditionally expressed in podocytes using Nphs2-Cre and LacZfloxed QLα12 transgenic mice. Some QLα12\(^{LacZ+/Cre+}\) mice developed proteinuria at 4-6m, and most were proteinuric by 12m. Proteinuria increased with age, and by 12-14m many demonstrated glomerulosclerosis with ultrastructural changes including foot process fusion and both mesangial and subendothelial deposits. QLα12\(^{LacZ+/Cre+}\) mice showed no changes in podocyte number, apoptosis, proliferation, or Rho/Src activation. Real-time PCR revealed no significant changes in Nphs1, Nphs2, Cd2ap, or Trpc6 expression, but Col4a2 message was increased in younger and older mice while Col4a5 was decreased in older mice. Confocal microscopy revealed disordered collagen IVα1/2 staining in older mice and loss of α5 without changes in other collagen IV subunits. Taken together, these studies suggest that Gα12 activation promotes glomerular injury without podocyte depletion through a novel mechanism regulating collagen (α)IV expression, and supports the notion that glomerular damage may accrue through persistent GPCR activation in podocytes.
Published Version: doi:10.1038/labinvest.2011.198
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338890/pdf/
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Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10589816
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