cGAS-Sting Activation Contributes to Podocyte Injury in Diabetic Kidney Disease

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

Publication Date

10-21-2022

Journal

iScience

DOI

10.1016/j.isci.2022.105145

PMID

36176590

PMCID

PMC9513272

PubMedCentral® Posted Date

9-16-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Biological sciences, molecular biology, diabetology

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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