Renalase Prevents Renal Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Down-Regulating GSK-3β/Snail Signaling

Background: Treating renal fibrosis is crucial to delaying chronic kidney disease. The glycogen synthase kinase-3β (GSK-3β)/Snail pathway regulates renal fibrosis and Renalase can ameliorate renal interstitial fibrosis. However, it is not clear whether GSK-3β/Snail signaling affects Renalase action. Here, we explored the role and mechanism of GSK-3β/Snail in the anti-fibrosis action of Renalase. Materials and methods: We used mice with complete unilateral ureteral obstruction (UUO) and human proximal renal tubular epithelial (HK-2) cells with transforming growth factor-β1 (TGF-β1)-induced fibrosis to explore the role and regulatory mechanism of the GSK-3β/Snail pathway in the amelioration of renal fibrosis by Renalase. Results: In UUO mice and TGF-β1-induced fibrotic HK-2 cells, the expression of p-GSK-3β-Tyr216/p-GSK-3β-Ser9, GSK-3β and Snail was significantly increased, and endoplasmic reticulum (ER) stress was activated. After Renalase supplementation, fibrosis was alleviated, ER stress was inhibited and p-GSK-3β-Tyr216/p-GSK-3β-Ser9, GSK-3β and Snail were significantly down-regulated. The amelioration of renal fibrosis by Renalase and its inhibitory effect on GSK-3β/Snail were reversed by an ER stress agonist. Furthermore, when an adeno-associated virus or plasmid was used to overexpress GSK-3β, the effect of Renalase on delaying renal fibrosis was counteracted, although ER stress markers did not change. Conclusion: Renalase prevents renal fibrosis by down-regulating GSK-3β/Snail signaling through inhibition of ER stress. Exogenous Renalase may be an effective method of slowing or stopping chronic kidney disease progression.