Role of RAS/Wnt/β-catenin axis activation in the pathogenesis of podocyte injury and tubulo-interstitial nephropathy

Renin-angiotensin system (RAS) plays a key role in the development and progression of chronic kidney disease (CKD). Recent studies have demonstrated activation of Wnt/beta-catenin pathway by RAS in CKD. However, the underlying mechanisms of RAS and Wnt/beta-catenin signaling interaction and their contribution to the pathogenesis of CKD have not been fully elucidated. Present study is designed to investigate the role of RAS/Wnt/beta-catenin axis activation in tubulo-interstitial fibrosis and glomerulosclerosis by the cultured HK-2 and podocytes. HK-2 cells and podocytes are treated by angiotensin II (Ang II). Ang II up-regulates expression of various Wnt mRNA and active beta-catenin protein in HK-2 cells and podocytes in the time- and dose-dependent manners. In addition, Ang II induces injury, oxidative stress and inflammation and impaired Nrf2 activation in HK-2 cells and podocytes. This was accompanied by up-regulations of RAS components as well as Wnt1, activated beta-catenin and its target proteins. RAS/Wnt/beta-catenin axis activation results in epithelial-to-mesenchymal transition in HK-2 cells and injuries podocytes. The effect of Ang II is inhibited by losartan and ICG-001, a Wnt/beta-catenin inhibitor. We further found that treatment with natural products, ergone, alisol B 23-acetate and pachymic acid B inhibit extracellular matrix accumulation in HK-2 cells and attenuated podocyte injury, in part, by inhibiting Ang II induced RAS/Wnt/beta-catenin axis activation. In summary, activation of RAS/Wnt/beta-catenin axis results in podocytes and tubular epithelial cell, injury and up-regulations of oxidative, inflammatory and fibrotic pathways. These adverse effects are ameliorated by ergone, alisol B 23-acetate and pachymic acid B. Therefore, these natural products could be considered as novel Wnt/beta-catenin signaling inhibitors and anti-fibrotic agents. (C) 2017 Elsevier B.V. All rights reserved.