#3197 Cardio-renal butterfly effect: myocardial infarction with coronary reperfusion triggers kidney disease and induces interstitial fibrosis

Abstract Background and Aims Chronic cardiovascular and kidney disorder (CCKD) remains a challenge in healthcare, characterized by the intricate interplay between cardiac and renal diseases. Acute cardio-renal aggressions are frequent and have significant long-term prognostic implications. Moreover, growing evidence supports the concept of the cardio-renal butterfly effect, whereby an acute cardiorenal event initiates a vicious cycle of organ crosstalk, impacting both the affected and distant organs. While the remote cardiac repercussions of acute renal failure are well-documented, the reverse relationship remains to be explored. The aim of this study was to describe the histological, biochemical, and molecular-scale renal dysfunctions following a coronary ischemia-reperfusion injury (IRI). Method We used a coronary IRI model in wild-type mice (C57B6) consisting with a reversible ligation of the left anterior descending artery of 1-hour. Sham operated mice underwent a thoracotomy without IRI. Histological, biochemistry and transcriptomics (RNAseq) were performed on kidney tissue from mice at day 1, 7 or 28 after IRI. Results Using Masson's trichrome staining, a significant increase in renal interstitial fibrosis was observed in mice following IRI (2% for IRI versus 1%, P = 0.028, Fig. 1). Plasma measurements exhibited a significant elevation of urea in IRI mice (median urea 6.97 mmol/L for sham versus 8.44 mmol/L, P = 0.018 for IRI). At D28, Western blot analysis on kidney tissue indicated a trend towards increased KIM-1 expression, while NGAL levels remained unchanged after IRI. At D7, renal transcriptome analysis revealed a deregulation of genes involved in kidney disease, as well as in heart failure and myocardial infarction. Interestingly, genes associated with metabolic syndrome, obesity, and diabetes were also affected. Notably, qPCR showed a significantly lower expression of PPARα and PPARγ genes in IRI mice at D7. At D28, renal transcriptome analysis further demonstrated a deregulation of genes linked to chronic kidney disease and heart failure, along with genes involved in mitochondrial function. For instance, Western blot analysis at D28 revealed a decreased expression of PGC1α and SOD2 proteins, confirming persistent mitochondrial dysfunction in the kidneys of IRI mice. Conclusion In a murine model, myocardial infarction with coronary reperfusion triggers kidney disease, induces interstitial fibrosis associated with probable mitochondrial dysfunction. Further research is needed to understand the pathophysiology.