Renal denervation normalizes NKCC2 abundance in rats with congestive heart failure

Abstract

Congestive heart failure (CHF) is associated with increased sympathetic nerve activity (SNA) and recent studies have shown increased abundance of the Na,K,2Cl-cotransporter (NKCC2) within the thick ascending limb of Henles loop (TAL) in CHF rats. We investigated the role of bilateral renal denervation (DNX) on the expression of NKCC2 and the sodium proton exchanger NHE3 within the outer medulla in rats with CHF induced by ligation of the left anterior descending coronary artery. Sham operated rats were used as controls. Western blotting on outer medullary homogenates showed an increase in NKCC2 protein level by ~256% and NHE3 protein level by ~245% in the CHF rats. DNX normalized the expression of NKCC2 but had no effect on NHE3. In addition to this we also examined the effect of DNX on basal levels of cAMP in isolated TAL CHF and sham operated controls. DNX significantly decreased the cAMP concentration in both Sham-operated controls and CHF rats (SHAM: 4.7 ± 1.4 vs. DNX-SHAM: 2.4 ± 1.5 fmol cAMP/μg protein; CHF: 12.6 ± 7.7 vs. DNX-CHF: 7.9 ± 4.3 fmol cAMP/μg protein) Finally we measured cAMP accumulation in response to vasopressin (AVP) in isolated TAL and found that DNX significantly reduced the maximal response to AVP in both Sham and CHF rats DNX-CHF: 67% of CHF; Sham-DNX: 28% of Sham. Together these results suggest that SNA have profound effects on outer medullary TAL function and that increased SNA activity plays a central role for the increased NKCC2 abundance found in rats with CHF. This work received financial support from the Danish Heart Foundation