Renal Semaphorin 3C mediates cardiac adaptive response

Abstract Cardiorenal syndrome, characterized by reciprocal heart-kidney interactions that progressively promote dysfunction in both organs, is associated with a high mortality rate. However, the mechanisms linking the two organs are insufficiently understood. Here we report that semaphorin 3C (SEMA3C) is a novel cardioprotective mediator secreted from the kidney. SEMA3C was highly expressed in the renal proximal tubules in mice. Renal Sema3c expression and circulating SEM3C were reduced by the left ventricular pressure overload that induced renal remodeling. Proximal tubule-specific secretory Sema3c deletion exacerbated cardiac hypertrophy, fibrosis and dysfunction after the pressure overload, suggesting renal SEMA3C is important for the proper cardiac adaptive response. Mechanistically, SEMA3C inhibits pathological cardiac remodeling at least partly by inhibiting Akt, ERK and Wnt/β-catenin signaling in cardiomyocytes. In heart failure patients, the plasma SEMA3C level was decreased and the low plasma SEMA3C was associated with poor cardiac outcomes. Collectively, our results show that SEMA3C produced by the kidney pivotally contributes to the cardiac stress response and its reduction contributes to the progression of heart failure. SEMA3C signaling appears to be an attractive therapeutic and diagnostic target for cardiorenal syndrome.