Renalase Prevents Renal Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Down-Regulating GSK-3β/Snail Signaling.
Renalase Prevents Renal Fibrosis by Inhibiting Endoplasmic Reticulum Stress and Down-Regulating GSK-3β/Snail Signaling.
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肾氨酸酶通过抑制内质网应激和下调GSK-3β/Snail信号通路来预防肾纤维化。
DOI：
10.7150/ijms.82192
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发表时间：
2023
影响因子：
3.6
通讯作者：
Liu W
中科院分区：
文献类型：
--
作者：
Wu Y;Bai Y;Feng Y;Zhang Q;Diao Z;Liu W
背景：治疗肾纤维化是延缓慢性肾脏疾病的关键。糖原合成酶激酶-3β (GSK-3β)/Snail通路调节肾纤维化，Renalase可改善肾间质纤维化。然而，GSK-3β/Snail信号传导是否影响Renalase的作用尚不清楚。本文探讨GSK-3β/Snail在Renalase抗纤维化中的作用及其机制。材料和方法：以完全性单侧输尿管梗阻（UUO）小鼠和转化生长因子-β1 （TGF-β1）诱导纤维化的人肾小管近端上皮（HK-2）细胞为研究对象，探讨GSK-3β/Snail通路在Renalase改善肾纤维化中的作用及调控机制。结果：在UUO小鼠和TGF-β1诱导的纤维化HK-2细胞中，p-GSK-3β-Tyr216/p-GSK-3β-Ser9、GSK-3β和Snail的表达显著升高，内质网应激被激活。补充Renalase后，纤维化减轻，内质网应激受到抑制，p-GSK-3β-Tyr216/p-GSK-3β-Ser9、GSK-3β和Snail蛋白显著下调。Renalase对肾纤维化的改善作用及其对GSK-3β/Snail的抑制作用被内质网应激激动剂逆转。此外，当使用腺相关病毒或质粒过表达GSK-3β时，Renalase延缓肾纤维化的作用被抵消，尽管内质网应激标志物没有改变。结论：Renalase通过抑制内质网应激，下调GSK-3β/Snail信号通路，从而预防肾纤维化。外源性Renalase可能是减缓或停止慢性肾脏疾病进展的有效方法。
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.
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