Interleukin-33 Mediates Cardiomyopathy After Acute Kidney Injury by Signaling to Cardiomyocytes

Abstract

BACKGROUND: Acute kidney injury (AKI) is a short-term life-threatening condition that, if survived, can lead to renal insufficiency and development of chronic kidney disease. The pathogenesis of AKI and chronic kidney disease involves direct effects on the heart and the development of hypertrophy and cardiomyopathy. METHODS: We used mouse models of ischemia/reperfusion AKI and unilateral ureteral obstruction to investigate the role of IL-33 (interleukin-33) and its receptor-encoding gene Il1rl1 (also called ST2L [suppression of tumorigenicity 2]) in cardiac remodeling after AKI. Mice with cell type–specific genetic disruption of the IL-33/ST2L axis were used, and IL-33 monoclonal antibody, adeno-associated virus encoding IL-33 or ST2L, and recombinant IL-33, as well. RESULTS: Mice deficient in Il33 were refractory to cardiomyopathy associated with 2 models of kidney injury. Treatment of mice with monoclonal IL-33 antibody also protected the heart after AKI. Moreover, overexpression of IL-33 or injection of recombinant IL-33 induced cardiac hypertrophy or cardiomyopathy, or both, but not in mice lacking Il1rl1 . AKI-induced cardiomyopathy was also reduced in mice with cardiac myocyte–specific deletion of Il1rl1 but not in endothelial cell- or fibroblast-specific deletion of Il1rl1 . Last, overexpression of the ST2L receptor in cardiac myocytes recapitulated induction of cardiac hypertrophy. CONCLUSIONS: These results indicate that IL-33 released from the kidney during AKI underlies cardiorenal syndrome by directly signaling to cardiac myocytes, suggesting that antagonism of IL-33/ST2 axis would be cardioprotective in patients with kidney disease.

Mechanistic role of RND3-regulated IL33/ST2 signaling on cardiomyocyte senescence

“…Under normal conditions, IL33 is expressed in the cell nucleus and is secreted extracellularly in cases of infection, in ammation, tissue injury, and cell necrosis [5,26]. IL33 binds to its transmembrane receptor, ST2L, and the activated IL33/ST2 signal participates in critical pathophysiological processes including in ammation, brosis, and heart failure [27][28][29][30], suggesting the IL-33/ST2 pathway has broad clinical translational potential. The mechanism of increased intracellular IL33 expression remains unclear, but some studies suggest that Yap/Taz can directly regulate the IL33 promoter and promote its expression in cardiac broblasts [31].…”

Mechanistic role of RND3-regulated IL33/ST2 signaling on cardiomyocyte senescence

“…Under normal circumstances, IL33 is expressed in the nucleus of the cell, and it is secreted to the outside of the cell in cases of infection, in ammation, tissue injury and cell necrosis [5,26]. IL33 binds to its transmembrane receptor, ST2L, and the activated IL33/ST2 signal is involved in important pathophysiological processes including in ammation, brosis, and heart failure [27][28][29][30], so it is considered that the IL-33/ST2 pathway has extensive clinical transformation value. The mechanism of increased intracellular IL33 expression remains unclear, but some studies have suggested that Yap/Taz can directly regulate the IL33 promoter and promote its expression in cardiac broblasts [31].…”

“…The biological role of IL33/ST2 signaling in cardiomyocytes is controversial. It has been reported that IL33 released after acute kidney injury can induce cardiomyocyte hypertrophy, showing a pathogenic effect [29], while in diabetic cardiomyopathy mice, IL33 administration can block autophagy and enhance cardiac diastolic function, thus having a protective effect [30]. In this study, we found that cardiomyocytes showed a signi cant SASP after administration of exogenous IL33, which was manifested as increased expression of SASP such as MCP1, IL1α and IL6, as well as increased number of SA-β-galactosidase active cells and the trend of cellular DNA damage, suggesting that the increase of IL33 has a damaging effect on cardiomyocytes.…”

Unraveling Chronic Cardiovascular and Kidney Disorder through the Butterfly Effect

“…However, some studies associate IL33 with worse cardiac outcomes, particularly post myocardial infarction [ 153 ]. Our research demonstrates that IL33 directly contributes to cardiac remodeling post AKI through the ST2 receptor on cardiomyocytes [ 154 ]. IL33 overexpression in mice led to a detrimental cardiac phenotype, whereas blocking IL33 during AKI protected the heart.…”