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

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 QLα12LacZ+/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. QLα12LacZ+/Cre+ mice showed no changes in podocyte number, apoptosis, proliferation, or Rho/Src activation. Real-tim