| First Author | Boucher I | Year | 2012 |
| Journal | Lab Invest | Volume | 92 |
| Issue | 5 | Pages | 662-75 |
| PubMed ID | 22249312 | Mgi Jnum | J:183428 |
| Mgi Id | MGI:5318655 | Doi | 10.1038/labinvest.2011.198 |
| Citation | Boucher I, et al. (2012) Galpha12 activation in podocytes leads to cumulative changes in glomerular collagen expression, proteinuria and glomerulosclerosis. Lab Invest 92(5):662-75 |
| abstractText | Glomerulosclerosis is a common pathological 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. Galpha12 couples to numerous G-protein-coupled receptors (GPCRs) and regulates multiple epithelial responses, including proliferation, apoptosis, permeability and the actin cytoskeleton. Herein, we report that genetic activation of Galpha12 in podocytes leads to time-dependent increases in proteinuria and glomerulosclerosis. To mimic activation of Galpha12 pathways, constitutively active Galpha12 (QL) was conditionally expressed in podocytes using Nphs2-Cre and LacZ/floxed QLalpha12 transgenic mice. Some QLalpha12(LacZ+/Cre+) mice developed proteinuria at 4-6 months, and most were proteinuric by 12 months. Proteinuria increased with age, and by 12-14 months, many demonstrated glomerulosclerosis with ultrastructural changes, including foot process fusion and both mesangial and subendothelial deposits. QLalpha12(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 IValpha1/2 staining in older mice and loss of alpha5 without changes in other collagen IV subunits. Taken together, these studies suggest that Galpha12 activation promotes glomerular injury without podocyte depletion through a novel mechanism regulating collagen (alpha)IV expression, and supports the notion that glomerular damage may accrue through persistent GPCR activation in podocytes. |
