The Cardiorenal Effects of IL-33 Treatment in Myocardial Infarction-Induced Kidney Damage

Abstract

Myocardial infarction (MI) is a major public health concern and a leading cause of acute kidney injury through the cardio-renal interrelationship, otherwise known as type I cardio-renal syndrome. Interleukin (IL)-33, a member of the IL-1 superfamily, is a nuclear alarmin released upon tissue damage and necrosis, binding thereafter to ST2 receptors, eliciting consequently an inflammatory response. Strong published evidence reported an emerging role of the IL-33/ST2 axis in different models of kidney diseases including drug-induced nephrotoxicity and kidney ischemia-reperfusion. Although the IL-33/ST2 axis was shown to be involved in the pathogenesis of kidney diseases, pre-clinical investigations indicated potential protective roles for the IL-33 signaling pathway. In this study, we aimed at investigating the effect of IL-33 administration on kidney damage at 4 and 7 days post-MI in C57BL6/J male mice. MI was induced by ligating the left anterior descending artery, followed by IL-33 (1μg/day) /vehicle (PBS) treatment for 4, 7 days post-MI. Cardiac systolic function and systemic inflammation were assessed, and kidneys were subjected to histological and molecular analysis. Cardiac hemodynamic assessment revealed exacerbated left ventricular systolic function characterized by a more significant decrease in EF and FS in the IL-33 treated group day 7 post-MI when compared to vehicle treated MI group. In agreement, cardiac sST2 mRNA expression levels markedly increased at day 7 in the IL-33 treated MI when compared to the vehicle treated MI group. Systemic inflammation assessment revealed a significant decrease in plasma TNF-α levels at 4 days but a substantial increase in plasma IL-1β at 7 days in the IL-33 treated MI group compared to the vehicle treated MI group. At the level of the kidneys, IL-33 treatment post-MI induced morphological alterations characterized by a significant decrease in Bowman’s capsule area and glomerular retraction at day 4 only when compared to vehicle treated MI group. Nevertheless, a significant decrease in renal fibrosis with IL-33 treatment 4 days post-MI relative to vehicle treated MI group was faced by a significant increase at day 7. Molecularly, total renal ROS score significantly increased in IL-33 treated MI group when compared to vehicle treated MI mice, while remained unchanged at day 7. Conversely, IL-33 treatment significantly decreased renal pro-fibrotic markers including α-smooth muscle actin (α-SMA) and collagen 3 (COL3) and the apoptotic regulatory genes such as Bcl-2-associated X protein/B-cell lymphoma 2 ratio 4 days post-MI. At 7 days post-MI however, renal α-SMA and COL3 significantly increased in the IL-33 treated MI group while no significant change in BAX/BCL2 ratio was observed. Metabolically, IL-33 treatment significantly increased NAD and SIRT3 mRNA expression levels at day 4, but not at day 7 post-MI. Collectively, our findings reveal that although IL-33 treatment seems to improve renal homeostasis as early as 4 days post-MI, this protection seems to be offset as early as day 7 post-MI which correlates with aggravating adverse LV remodeling. Further investigation is required to conclude whether the adverse impact of IL-33 treatment on the kidneys is direct or fueled by the exacerbation of cardiac remodeling at 7 days post-MI.