Sirt6 Deficiency Contributes to Mitochondrial Fission and Oxidative Damage in Podocytes Via ROCK1-Drp1 Signalling Pathway

Overview

Journal Cell Prolif

Date 2022 Jul 17

PMID 35842903

Authors

Zhaowei Chen

Wei Liang

Jijia Hu

Zijing Zhu

Jun Feng

Yiqiong Ma

Qian Yang

Guohua Ding

Affiliations

Soon will be listed here.

Abstract

Objectives: Increasing evidence suggests that mitochondrial dysfunction is the key driver of angiotensin II (Ang II)-induced kidney injury. This study was designed to investigate whether Sirtuin 6 (Sirt6) could affect Ang II-induced mitochondrial damage and the potential mechanisms.

Materials And Methods: Podocyte-specific Sirt6 knockout mice were infused with Ang II and cultured podocytes were stimulated with Ang II to evaluate the effects of Sirt6 on mitochondrial structure and function in podocytes. Immunofluorescence staining was used to detect protein expression and mitochondrial morphology in vitro. Electron microscopy was used to assess mitochondrial morphology in mice. Western blotting was used to quantify protein expression.

Results: Mitochondrial fission and decreased Sirt6 expression were observed in podocytes from Ang II-infused mice. In Sirt6-deficient mice, Ang II infusion induced increased apoptosis and mitochondrial fragmentation in podocytes than that in Ang II-infused wild-type mice. In cultured human podocytes, Sirt6 knockdown exacerbated Ang II-induced mitochondrial fission, whereas Sirt6 overexpression ameliorated the Ang II-induced changes in the balance between mitochondrial fusion and fission. Functional studies revealed that Sirt6 deficiency exacerbated mitochondrial fission by promoting dynamin-related protein 1 (Drp1) phosphorylation. Furthermore, Sirt6 mediated Drp1 phosphorylation by promoting Rho-associated coiled coil-containing protein kinase 1 (ROCK1) expression.

Conclusion: Our study has identified Sirt6 as a vital factor that protects against Ang II-induced mitochondrial fission and apoptosis in podocytes via the ROCK1-Drp1 signalling pathway.

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