cGAS-STING activation contributes to podocyte injury in diabetic kidney disease
Summary: 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-10-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222014171 |
| _version_ | 1811204741544280064 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Nan Zang |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-12T03:17:48Z |
| format | Article |
| id | doaj.art-999b97fb2a624fec84350ac2aadc4b9d |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-12T03:17:48Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-999b97fb2a624fec84350ac2aadc4b9d2022-12-22T03:50:00ZengElsevieriScience2589-00422022-10-012510105145cGAS-STING activation contributes to podocyte injury in diabetic kidney diseaseNan Zang0Chen Cui1Xinghong Guo2Jia Song3Huiqing Hu4Mengmeng Yang5Mingyue Xu6Lingshu Wang7Xinguo Hou8Qin He9Zheng Sun10Chuan Wang11Li Chen12Department of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan, Shandong 250012, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan, Shandong 250012, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, Shandong 250012, ChinaDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan, Shandong 250012, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, Shandong 250012, ChinaDepartment of Medicine – Endocrinology, Baylor College of Medicine, Houston, TX, USADepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan, Shandong 250012, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, Shandong 250012, China; Corresponding authorDepartment of Endocrinology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China; Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, Shandong 250012, China; Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine and Health, Jinan, Shandong 250012, China; Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, Shandong 250012, China; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222014171Biological sciencesmolecular biologydiabetology |
| spellingShingle | 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 cGAS-STING activation contributes to podocyte injury in diabetic kidney disease iScience Biological sciences molecular biology diabetology |
| title | cGAS-STING activation contributes to podocyte injury in diabetic kidney disease |
| title_full | cGAS-STING activation contributes to podocyte injury in diabetic kidney disease |
| title_fullStr | cGAS-STING activation contributes to podocyte injury in diabetic kidney disease |
| title_full_unstemmed | cGAS-STING activation contributes to podocyte injury in diabetic kidney disease |
| title_short | cGAS-STING activation contributes to podocyte injury in diabetic kidney disease |
| title_sort | cgas sting activation contributes to podocyte injury in diabetic kidney disease |
| topic | Biological sciences molecular biology diabetology |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222014171 |
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