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Emodin Inhibits AIM2 Inflammasome Activation via Modulating K27-Linked Polyubiquitination to Attenuate Renal Fibrosis
Lidan Lu1, Ruonan Shuang2, Fang Cao3
1Department of Gynaecology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China.
Abstract:
Chronic kidney diseases (CKD) is a serious threat to people's health with renal fibrosis as the major pathological feature. The absent in melanoma 2 (AIM2) has recently been proposed to play a critical role in CKD. Emodin is a major bioactive compound from rhubarb, which is widely used for clinical treatment of renal disease. The aim of this study is to elucidate the effect of emodin on unilateral ureteral obstruction (UUO) model mice and its association with the AIM2 inflammasome. In this study, we established the UUO-induced mice renal interstitial fibrosis in vivo and bone marrow-derived macrophages (BMDMs) model in vitro. The BUN, SCr, TNF-α, IL-1β in serum were examined. The degree of renal damage and fibrosis were determined by histological assessment. Immunofluorescence, western blot, and Co-IP were used to determine the mechanisms of emodin against CKD. Emodin could improve UUO-induced abnormal renal function and histopathological abnormalities. It could also ameliorate renal fibrosis, evidenced by inhibiting the expression of α-SMA, TGF-β1, FN, and collagen I. Mechanistically, emodin significantly suppressed AIM2 inflammasome as well as its components including ASC, cleaved caspase-1, and IL-1β both in vivo and in vitro. Further studies demonstrated that emodin inhibited K27-linked polyubiquitination of AIM2 by targeting on K64 sites of the lysine residues. In summary, emodin could hinder the activation of AIM2 inflammasome in UUO model mice through K27-linked polyubiquitination to reduce renal fibrosis. Emodin is a possible therapeutic option for CKD treatment.
Insights
Emodin, a compound from rhubarb, reduces kidney fibrosis in mice by inhibiting the AIM2 inflammasome pathway. This study suggests emodin as a potential therapeutic for chronic kidney diseases (CKD).
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Chronic kidney diseases (CKD) present a significant global health challenge, characterized by progressive renal fibrosis.
- The Absent in Melanoma 2 (AIM2) inflammasome is increasingly recognized for its role in the pathogenesis of CKD.
- Emodin, a natural compound found in rhubarb, possesses known therapeutic properties for renal conditions.
Purpose of the Study:
- To investigate the therapeutic effects of emodin on unilateral ureteral obstruction (UUO)-induced renal fibrosis in a mouse model.
- To elucidate the underlying mechanisms, particularly the involvement of the AIM2 inflammasome pathway.
Main Methods:
- Establishment of UUO-induced renal interstitial fibrosis in vivo and bone marrow-derived macrophages (BMDMs) model in vitro.
- Assessment of renal function (BUN, SCr) and inflammatory markers (TNF-α, IL-1β).
- Histological analysis, immunofluorescence, western blot, and Co-immunoprecipitation (Co-IP) to evaluate fibrosis and molecular pathways.
Main Results:
- Emodin treatment improved renal function and ameliorated histopathological damage in UUO mice.
- Emodin significantly reduced markers of renal fibrosis, including α-SMA, TGF-β1, FN, and collagen I.
- Emodin suppressed AIM2 inflammasome activation, including ASC, cleaved caspase-1, and IL-1β, by inhibiting K27-linked polyubiquitination of AIM2 at K64.
Conclusions:
- Emodin effectively mitigates renal fibrosis in a preclinical model of CKD.
- The mechanism involves the inhibition of AIM2 inflammasome activation via targeted deubiquitination.
- Emodin demonstrates potential as a novel therapeutic agent for managing chronic kidney diseases.
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