Previously we have shown that increased expression of renal epithelial sodium channels (ENaC) subunits may contribute to the renal sodium and water retention observed during chronic heart failure (CHF). The goal of this study was to examine whether renal denervation (RDN) changes the expression of aquaporin 2 (AQP2) and two major renal sodium transporters ENaC and sodium‐hydrogen exchanger‐3 proteins (NHE3)] in rats with CHF. CHF was produced by left coronary artery ligation in rats. Four weeks after ligation surgery, bilateral RDN were performed. Western blot analysis indicated that RDN (one week later) significantly reduced enhanced protein levels of AQP2 (1.30±0.20 vs. 0.33±0.09, P<0.05), alpha‐ENaC (0.43±0.09 vs. 0.25±0.06, P<0.05), beta‐ENaC (0.11±0.03 vs. 0.05 ± 0.01, P<0.05) and gamma‐ENaC (0.89±0.15 vs. 0.44±0.09, P<0.05) subunits in the renal cortex of CHF rats compared to the CHF non‐denervated group. RDN had no significant effects on the protein expression of kidney NHE3 in both sham and CHF rats. These findings suggest a critical role for renal nerves in the enhanced expression of AQP2 and ENaC and subsequent pathophysiology of renal water and sodium retention associated with CHF.Support or Funding InformationSupported by NIH grants HL124104 and HL62222