Acute Kidney Injury Disrupts Cardiac Remodeling via SerpinA3N.

Abstract

BACKGROUND: Cardiorenal syndrome type 3 describes cardiac injury triggered by acute kidney injury (AKI). AKI caused by ischemia reperfusion injury represents a model for kidney injury during kidney transplant. It is well known that kidney transplant recipients are at increased risk to develop cardiac fibrosis; however, the molecular mechanisms linking renal injury to myocardial remodeling or cardiac fibrosis remain unclear. METHODS: Using a C57BL/6J mouse model of ischemia reperfusion injury-AKI, we combined proteomics and RNA seqencing transcriptomics to define early cardiac responses. We validated the proteomics and RNA sequencing data with quantitative polymerase chain reaction, ELISA, cytokine array, and western blotting for profibrotic and injury markers. We assessed SerpinA3N function using a granzyme B activity assay kit and XAV939, an inhibitor of SerpinA3N. Ingenuity pathway analysis further confirmed serine protease activity inhibition and increased expression of cardiac fibrosis-related genes after AKI. RESULTS: Successful establishment of renal ischemia reperfusion injury causing AKI, followed by significant induction of cardiac injury. AKI significantly upregulated SerpinA3N in the heart while suppressing serine protease (granzyme B) activity. Concomitantly, AKI hearts displayed elevated profibrotic genes (FN1, COL1A1, TGF-β1), mitochondrial dysfunction, and heightened inflammatory signaling. In vitro, inhibition of SerpinA3N with XAV939 restored granzyme B activity, confirming direct suppression by SerpinA3N. CONCLUSIONS: We conclude that SerpinA3N serves as a key mediator of cardiorenal syndrome type 3 pathogenesis, by inhibiting granzyme B, which promotes profibrotic remodeling in the heart following AKI. Targeting SerpinA3N could be a potential therapeutic approach that restores balanced extracellular matrix turnover and mitigates cardiac fibrosis.

Abstract as supplied by the indexing source. © the authors / publisher.