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.

• Authors: Lin Chen, Dan-Qian Chen, Ming Wang, Dan Liu, Hua Chen, Fang Dou, Nosratola D Vaziri, Ying-Yong Zhao
• Journal: Chemico-biological interactions (Chem Biol Interact) Vol. 273 Pg. 56-72 (Aug 01 2017) ISSN: 1872-7786 [Electronic] Ireland
• PMID: 28578904 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• ICG 001
• Pyrimidinones
• Wnt Proteins
• beta Catenin
• Angiotensin II
• Losartan

Topics

• Angiotensin II (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Humans
• Kidney Tubules (drug effects, metabolism, pathology)
• Losartan (pharmacology)
• Nephritis, Interstitial (drug therapy, metabolism, pathology)
• Podocytes (drug effects, metabolism, pathology)
• Pyrimidinones (pharmacology)
• Renin-Angiotensin System (drug effects)
• Structure-Activity Relationship
• Wnt Proteins (antagonists & inhibitors, metabolism)
• beta Catenin (antagonists & inhibitors, metabolism)