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

Abstract

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/β-catenin pathway by RAS in CKD. However, the underlying mechanisms of RAS and Wnt/β-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/β-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 β-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 β-catenin and its target proteins. RAS/Wnt/β-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/β-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/β-catenin axis activation. In summary, activation of RAS/Wnt/β-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/β-catenin signaling inhibitors and anti-fibrotic agents.

New insights into TGF-β/Smad signaling in tissue fibrosis

“…Our results indicated that AR treatment retarded renal fibrosis by downregulating inflammation and TGF-β1/Smad pathway in CKD rats [108]. Our further study demonstrated that alisol B 23-acetate treatment significantly amileriated podocytes and tubular epithelial cells by inhibiting activation of Wnt/βcatenin, oxidative stress and inflammation [109]. 25-O-methylalisol F is a new tetracyclic triterpenoid compound isolated from the AR.…”

Small molecule inhibitors of epithelial‐mesenchymal transition for the treatment of cancer and fibrosis

“…Additionally, it was also observed that ergone inhibited extracellular matrix accumulation in HK-2 cells and attenuated podocyte injury through inhibiting the activation of the Wnt/β-catenin signaling pathway induced by angiotensin II. 81 Taken together, these data indicate that tetracyclic triterpenoid and steroid compounds show significant antifibrotic properties in renal fibrosis.…”

“…Our recent study demonstrated that triterpenoid was the main component of AR, and further study showed that the novel tetracyclic triterpenoid 25‐O‐methylalisol F inhibited EMT by suppressing the Wnt/β‐catenin signaling pathway as well as the phosphorylation of Smad3 signaling in both NRK‐52E and NRK‐49F cells (Figure and Table ). Additionally, it was also observed that ergone inhibited extracellular matrix accumulation in HK‐2 cells and attenuated podocyte injury through inhibiting the activation of the Wnt/β‐catenin signaling pathway induced by angiotensin II . Taken together, these data indicate that tetracyclic triterpenoid and steroid compounds show significant antifibrotic properties in renal fibrosis.…”

Tetrahydroxy stilbene glucoside protected against diabetes‐induced osteoporosis in mice with streptozotocin‐induced hyperglycemia

“…The results suggested that SOST/β‐catenin pathway might also be involved in the action of TSG on osteogenesis. Additionally, the recent studies showed the link between the local RAS and β‐catenin pathway in kidney (Chen et al, ; Wang et al, ), and the natural products contained in traditional herbal medicine, such as triterpenes (PZG and PZH) from Poria cocos (Wang et al, ) and 25‐O‐methylalisol F from Alismatis rhizome (Chen et al, ), were found to act as novel RAS inhibitors in attenuating renal fibrosis. The effects of TSG on the cross talk between these two pathways in bone need to be further investigated for better understanding the role and the action mechanism of TSG in maintaining bone health.…”