title: NLRP3 inflammasome activation is involved in Ang II-induced kidney damage via mitochondrial dysfunction.
abstract: Growing evidence has shown that NLRP3 inflammasome activation promotes the development of tubularinterstitial inflammation and progression of renal injury. We previously found that mitochondrial dysfunction is a critical determinant for the activation of NLRP3 inflammasome in albumin-overload rats. Angiotensin (Ang) II plays an important role in mitochondrial homeostasis. Here, we investigated the role of Ang II in NLRP3 inflammasome activation and the involvement of mitochondrial dysfunction in this process. In vitro, Ang II triggered NLRP3 inflammasome activation in a dose- and time-dependent manner, and this effect is mediated by AT1 receptor rather than AT2 receptor. MitoTEMPO, a mitochondrial targeted antioxidant, attenuated Ang II induced mitochondrial reactive oxygen species (mROS) production and NLRP3 inflammation activation. Following chronic Ang II infusion for 28 days, we observed remarkable tubular epithelial cells (TECs) injury, mitochondrial damage, and albuminuria in WT mice. However, these abnormalities were significantly attenuated in AT1 receptor KO mice. Then, we examined the role of mitochondria in Ang II-infused mice with or without mitoTEMPO treatment. As expected, Ang II-induced mitochondrial dysfunction and NLRP3 inflammasome activation was markedly inhibited by mitoTEMPO. Notably, NLRP3 deletion signally protected TECs from Ang II-triggered mitochondrial dysfunction and NLRP3 inflammasome activation. Taken together, these data demonstrate that Ang II induces NLRP3 inflammasome activation in TECs which is mediated by mitochondrial dysfunction.
authors: Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, Jiangsu, China.
authors: Yi
authors: Y
authors: Wen
authors: Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, Jiangsu, China.
authors: Yiran
authors: Y
authors: Liu
authors: Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, Jiangsu, China.
authors: Taotao
authors: T
authors: Tang
authors: Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, Jiangsu, China.
authors: Linli
authors: L
authors: Lv
authors: Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, Jiangsu, China.
authors: Hong
authors: H
authors: Liu
authors: Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, Jiangsu, China.
authors: Kunling
authors: K
authors: Ma
authors: Institute of Nephrology, Zhong Da Hospital, Southeast University, Nanjing, Jiangsu, China.
authors: Bicheng
authors: B
authors: Liu
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology*; D007684:Kidney Tubules / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000502:physiology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology
chemical_list: C555916:MitoTEMPO; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009943:Organophosphorus Compounds; D010880:Piperidines; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II
keywords: NLRP3 inflammasome; Pathology Section; RAS; mitochondrial dysfunction; angiotensin II