Enhanced levels of Proteases in Tubular Fluid Activate ENaC in Chronic Heart Failure: Roles for Renal Nerves and Renal Injury

Abstract

Previously we have shown increased proteases in the tubular fluid contribute to the enhanced epithelial sodium channels (ENaC) activity in chronic heart failure (CHF). In the present study, we hypothesized that activated renal nerves and podocyte injury are involved the enhanced levels of proteases in tubular fluid in CHF.CHF was produced by left coronary artery ligation in rats. Four weeks after ligation surgery, podocyte lesions were found in CHF rats by transmission electron microscopy. We also found that desmin expression, a marker for podocyte injury was enhanced in the podocyte of CHF rats by immunostaining and immunoblotting (increased ~2 folds). Renal adrenoceptors alpha1A and beta1, angiotensin II type 1 receptor expressions and aldosterone levels were significantly increased in both cortex and medulla in rats with CHF. Interestingly, one week after bilateral renal denervation (RDN) there was significant reduced levels of several urinary serine proteases (prostacin: reduced ~4 folds, plasminogen and plasmin: reduced ~2 folds) in rats with CHF. These findings provide strong evidence for the effects of renal nerves and renal injury on proteases in the kidneys of the CHF rats. Increased proteases in the tubular fluid may contribute to the enhanced ENaC activity, providing a novel mechanistic insight for sodium retention commonly observed in CHF.