Enos/no signaling regulates renal interstitial fibrosis by increasing cytoplasmic beta-catenin degradation

Renal interstitial fibrosis is a final common pathway in progressive renal disease. Recently, activation of the wnt/beta-catenin signaling pathway has been demonstrated to play an important role in the development of renal fibrosis. It is also well known that endothelial dysfunction is associated with chronic kidney disease. However, the role of endothelial dysfunction in the progression of renal fibrosis remains largely elusive. We hypothesized that protein kinase G (PKG) activation by nitric oxide (NO) could phosphorylate beta-catenin and downregulate beta-catenin signaling in the process of renal fibrosis. We showed that beta-catenin levels in the cytoplasm were decreased by activation of the NO-PKG pathway. Renal fibrotic changes were not observed in wild type (WT)-lithium (Li; glycogen synthase kinase-3beta inhibitor) mice. However, renal interstitial fibrosis developed in endothelial nitric oxide synthase knockout (eNOSKO)-Li mice compared with WT-Li mice. beta-catenin protein expression was remarkably increased in eNOSKO-Li mice. These changes were suppressed in eNOSKO-Li/Bay (soluble guanylate cyclase [sGC] stimulator) mice. Moreover, increased interstitial renal fibrosis was observed in eNOSKO mice subjected to unilateral ureteral obstruction (eNOSKO-UUO) compared with WT-UUO mice. beta-catenin protein expression was significantly increased in eNOSKO-UUO mice. These phenotypic changes in eNOSKO-UUO mice were suppressed by Bay treatment. Activation of eNOS signaling could be protective against renal interstitial fibrosis. These findings indicate the potential therapeutic utility of eNOS-NO-PKG stimulation for the amelioration of renal fibrosis.