cGAS-STING activation contributes to podocyte injury in diabetic kidney disease

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

doi:10.1016/j.isci.2022.105145

cGAS-STING activation contributes to podocyte injury in diabetic kidney disease

iScience. 2022 Sep 16;25(10):105145. doi: 10.1016/j.isci.2022.105145. eCollection 2022 Oct 21.

Authors

Nan Zang¹, Chen Cui¹, Xinghong Guo¹, Jia Song¹, Huiqing Hu¹, Mengmeng Yang¹, Mingyue Xu¹, Lingshu Wang^{1

2

3

4}, Xinguo Hou^{1

2

3

4}, Qin He^{1

2

3

4}, Zheng Sun⁵, Chuan Wang^{1

2

3

4}, Li Chen^{1

2

3

4}

Affiliations

¹ Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
² Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong 250012, China.
³ Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan, Shandong 250012, China.
⁴ Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, Shandong 250012, China.
⁵ Department of Medicine - Endocrinology, Baylor College of Medicine, Houston, TX, USA.

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.

Keywords: Biological sciences; diabetology; molecular biology.

Grants and funding

P30 ES030285/ES/NIEHS NIH HHS/United States