Abstract 15: The Cardio-renal Effects Of Il-33 Treatment In Myocardial Infarction-induced Kidney Damage

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Introduction: Interleukin (IL)-33 is a nuclear alarmin released upon tissue damage and initiating a signaling cascade by binding to its cell membrane receptor ST2. Accumulating evidence shows that the IL-33/ST2 axis mediates both inflammatory and repair responses in different models of kidney diseases, suggesting a Janus-like effect that varies within disease context and progression. This study aimed to investigate the effect of IL-33 administration on acute kidney damage at 4 and 7 days post-MI in mice. Methods: MI was induced by ligating the left anterior descending coronary artery, followed by IL-33 (1μg/day)/vehicle (PBS) treatment for 4 and 7 consecutive days. Cardiac systolic function was assessed, and kidneys were subjected to histological and molecular analysis. Results: IL-33 had no significant effect on cardiac hemodynamic parameters at 4 days but significantly decreased the left ventricular ejection fraction (20 ± 1 vs 9.8 ± 2, P<0.01) at 7 days post-MI. In the kidneys, reduced glomerular retraction (0.57 ± 0.09 vs 0.24 ± 0.06, P < 0.05) was observed at day 4 post-MI only, along with a decrease in the protein expression of αSMA (2.89 ± 0.33 vs 0.43 ± 0.13, P < 0.001) and collagen 3 (1.96 ± 0.78 vs 0.34 ± 0.14, P < 0.05). Conversely, increased protein levels of αSMA (0.86 ± 0.42 vs 21.5 ± 2.53, P < 0.0001) and collagen 3 (0.33 ± 0.08 vs 1.71 ± 0.22, P<0.01) were observed at day 7 post-MI. Total renal fibrosis increased to levels comparable to the MI vehicle group at day 4 and 7 post-MI. The mRNA expression of the apoptotic BAX/BCL2 ratio (1.05 ± 0.09 vs 0.36 ± 0.23, P < 0.05) decreased only at day 4 post-MI, whereas an increase in the mRNA levels of the DNA repair enzyme PARP-1 (1.37 ± 0.06 vs 2.05 ± 0.4, P<0.05) was observed at day 7 post-MI. A marked increase in the mRNA expression of Sirtuin 3 (1.87 ± 0.57 vs 11.72 ± 4.24, P < 0.05) and in total renal NAD levels (386.75 ± 40.52 vs 706.36 ± 66.09, P < 0.05) was observed at day 4 post-MI. Conclusion: Collectively, our findings suggest that although IL-33 treatment improves renal homeostasis 4 days post-MI, this protection is offset by day 7 post-MI through enhanced renal morphological and molecular alterations. The observed renal deterioration between day 4 and day 7 post-MI correlate with aggravated cardiac dysfunction.