AIM2 inflammasome contributes to aldosterone-induced renal injury via endoplasmic reticulum stress.

Yong Wu, Huan Yang, Sujuan Xu, Ming Cheng, Jie Gu, Weichen Zhang, Shaojun Liu, Minmin Zhang

Clinical science (London, England : 1979) 2022 Jan 14

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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. © 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Citation

Yong Wu, Huan Yang, Sujuan Xu, Ming Cheng, Jie Gu, Weichen Zhang, Shaojun Liu, Minmin Zhang. AIM2 inflammasome contributes to aldosterone-induced renal injury via endoplasmic reticulum stress. Clinical science (London, England : 1979). 2022 Jan 14;136(1):103-120