CGAS-STING Activation Contributes to Podocyte Injury in Diabetic Kidney Disease

Overview

Journal iScience

Publisher Cell Press

Date 2022 Sep 30

PMID 36176590

Authors

Nan Zang

Chen Cui

Xinghong Guo

Jia Song

Huiqing Hu

Mengmeng Yang

Mingyue Xu

Lingshu Wang

Xinguo Hou

Qin He

Zheng Sun

Chuan Wang

Li Chen

Affiliations

Soon will be listed here.

Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal diseases. DKD does not have efficacious treatment. The cGAS-STING pathway is activated in podocytes at the early stage of kidney dysfunction, which is associated with the activation of STING downstream effectors TBK1 and NF-κB but not IRF3. Lipotoxicity induces mitochondrial damage and mtDNA leakage to the cytosol through Bcl-2 associated X protein (BAX) in podocytes. BAX-mediated mtDNA cytosolic leakage can activate the cGAS-STING pathway in the absence of lipotoxicity and is sufficient to cause podocyte injury. Depletion of cytosolic mtDNA, genetic STING knockdown, or pharmacological inhibition of STING or TBK1 alleviates podocyte injury and improves renal functions in cultured podocytes or mouse models of diabetes and obesity. These results suggest that the mtDNA-cGAS-STING pathway promotes podocyte injury and is a potential therapeutic target for DKD or other obesity-related kidney diseases.

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