AIM2 inflammasome contributes to aldosterone-induced renal injury via endoplasmic reticulum stress. Issue 1 (14th January 2022)

• Record Type: Journal Article
• Authors: Wu, Yong; Yang, Huan; Xu, Sujuan; Cheng, Ming; Gu, Jie; Zhang, Weichen; Liu, Shaojun; Zhang, Minmin
• Is Part Of: Clinical science. Volume 136:Issue 1(2022)
• Page Start: 103
• Page End: 120
• Publication Date: 2022-01-14
• Subjects: AIM2 inflammasome -- Aldosterone -- Chronic kidney disease -- Endoplasmic reticulum stress -- Renal fibrosis; Medicine -- Periodicals; Biochemistry -- Periodicals; 616
• DOI: 10.1042/CS20211075
• Languages: English
• ISSNs: 0143-5221

Abstract

Abstract: Inflammatory response and renal fibrosis are the hallmarks of chronic kidney disease (CKD). However, the specific mechanism of aldosterone-induced renal injury in the progress of CKD requires elucidation. Emerging evidence has demonstrated that absent in melanoma 2 (AIM2)-mediated inflammasome activation and endoplasmic reticulum stress (ERS) play a pivotal role in the renal fibrosis. Here, we investigated whether overexpression or deficiency of AIM2 affects ERS and fibrosis in aldosterone-infused renal injury. Interestingly, we found that AIM2 was markedly expressed in the diseased proximal tubules from human and experimental CKD. Mechanically, overactivation of AIM2 aggravated aldosterone-induced ERS and fibrotic changes in vitro while knockdown of AIM2 blunted these effects in vivo and in vitro . By contrast, AIM2 deficiency ameliorated renal structure and function deterioration, decreased proteinuria levels and lowered systolic blood pressure in vivo ; silencing of AIM2 blocked inflammasome-mediated signaling pathway, relieved ERS and fibrotic changes in vivo . Furthermore, mineralocorticoid receptor (MR) antagonist eplerenone and ERS inhibitor tauroursodeoxycholic acid (TUDCA) had nephroprotective effects on the basis of AIM2 overactivation in vitro, while they failed to produce a more remarkable renoprotective effect on the treatment of AIM2 silence in vitro . Notably, the combination of TUDCA with AIM2 knockdown significantly reduced proteinuria levels in vivo . Additionally, immunofluorescence assay identified that apoptosis-associated speck-like protein (ASC) recruitment and Gasdermin-D (GSDMD) cleavage respectively occurred in the glomeruli and tubules in vivo . These findings establish a crucial role for AIM2 inflammasome in aldosterone-induced renal injury, which may provide a novel therapeutic target for the pathogenesis of CKD.