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

Abstract

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. 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 <i>Il1rl1</i> (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. Mice deficient in <i>Il33</i> 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, but not in mice lacking <i>Il1rl1</i>. AKI-induced cardiomyopathy was also reduced in mice with cardiac myocyte-specific deletion of <i>Il1rl1</i> but not in endothelial cell- or fibroblast-specific deletion of <i>Il1rl1</i>. Last, overexpression of the ST2L receptor in cardiac myocytes recapitulated induction of cardiac hypertrophy. 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.