刺
阿尔波特综合征
足细胞
医学
肾
免疫学
内科学
内分泌学
肾小球肾炎
蛋白尿
工程类
航空航天工程
作者
Alla Mitrofanova,Antonio Fontanella,Matthew Tolerico,Shamroop Kumar Mallela,Judith Molina,Yiqin Zuo,Maria Boulina,Jin Ju Kim,Javier Varona Santos,Mengyuan Ge,Alexis Sloan,Wadish Issa,Margaret Gurumani,Jeffrey D. Pressly,Mari Ito,Matthias Kretzler,Sean Eddy,Robert G. Nelson,Sandra Merscher,George W. Burke,Alessia Fornoni
出处
期刊:Journal of The American Society of Nephrology
日期:2022-12-01
卷期号:33 (12): 2153-2173
被引量:19
标识
DOI:10.1681/asn.2021101286
摘要
The signaling molecule stimulator of IFN genes (STING) was identified as a crucial regulator of the DNA-sensing cyclic GMP-AMP synthase (cGAS)-STING pathway, and this signaling pathway regulates inflammation and energy homeostasis under conditions of obesity, kidney fibrosis, and AKI. However, the role of STING in causing CKD, including diabetic kidney disease (DKD) and Alport syndrome, is unknown.To investigate whether STING activation contributes to the development and progression of glomerular diseases such as DKD and Alport syndrome, immortalized human and murine podocytes were differentiated for 14 days and treated with a STING-specific agonist. We used diabetic db/db mice, mice with experimental Alport syndrome, C57BL/6 mice, and STING knockout mice to assess the role of the STING signaling pathway in kidney failure.In vitro, murine and human podocytes express all of the components of the cGAS-STING pathway. In vivo, activation of STING renders C57BL/6 mice susceptible to albuminuria and podocyte loss. STING is activated at baseline in mice with experimental DKD and Alport syndrome. STING activation occurs in the glomerular but not the tubulointerstitial compartment in association with autophagic podocyte death in Alport syndrome mice and with apoptotic podocyte death in DKD mouse models. Genetic or pharmacologic inhibition of STING protects from progression of kidney disease in mice with DKD and Alport syndrome and increases lifespan in Alport syndrome mice.The activation of the STING pathway acts as a mediator of disease progression in DKD and Alport syndrome. Targeting STING may offer a therapeutic option to treat glomerular diseases of metabolic and nonmetabolic origin or prevent their development, progression, or both.
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