Acute kidney injury disrupts cardiac remodeling via SerpinA3N

Abstract

Cardiorenal syndrome type 3 (CRS-3) also known as acute reno-cardiac syndrome, refers to a condition where acute kidney injury (AKI) leads to acute cardiac dysfunction or injury. The underlying mechanisms have not been elucidated. In the current study, we examined the potential mechanisms for the development of myocardial pro-fibrotic factors and cardiac remodeling in C57BL/6J mice after AKI. The mice were subjected to bilateral pedicle clamping for 30 min followed by 24 h of reperfusion. Heart tissue was collected from control (Ctrl) and AKI mice and subjected to proteomic analysis by liquid chromatography-mass spectrometry (LC-MS) and differential mRNA expression analysis by RNA-seq. Cardiac tissue was collected to assess serine protease activity, RNA, protein and cytokine expression. The results indicate that AKI significantly upregulated SerpinA3N in the heart which was negatively correlated with serine protease (Granzyme B) activity. Further, AKI induced the development of several pro-fibrotic factors, induced mitochondrial dysfunction and increased inflammation. Finally, using H9C2 cells we demonstrated that inhibiting SerpinA3N with XAV939 increased Granzyme B activity. Thus, this study suggests that AKI leads to the development of pro-fibrotic factors in the heart and disrupts cardiac remodeling by SerpinA3N mediated inhibition of serine protease Granzyme B activity. Decreased SerpinA3N expression in the heart followed by AKI could lead to a more balanced extracellular matrix (ECM) composition in the heart with an alleviated pro-fibrotic response.