Sodium balance and resistance to Ang II‐induced hypertension, despite NCC and NKCC2 activation, in mice with global deletion of Na,K‐ATPase regulatory subunit FXYD2

Abstract

Na,K‐ATPase generates the driving force for sodium reabsorption in the kidney. Na,K‐ATPase functional properties are regulated by association with small proteins belonging to the FXYD family. Mice with global deletion of the inhibitory subunit, FXYD2, show 25% higher Na,K‐ATPase activity in renal cortex with no evidence of sodium retention. The hypothesis was that activation of basolateral Na,K‐ATPase in Fxyd2‐/‐ mice is compensated by adaptive reductions in apical Na+ transporters to maintain Na+ output equal to Na+ intake. Instead, there was an increase in expression and phosphorylation of sodium chloride co‐transporter, NCC, in DCT. The phosphorylation of the closely related apical NKCC2 also increased. NCC activation is commonly linked to development of renal hypertension. However, no elevation of blood pressure was evident in the knockout mice under resting conditions. Continuous infusion with Ang II (1 mg/kg, 7 days) resulted in an additional 2‐fold increase in phosphorylation of NCC at T53 and S71 in both WT and Fxyd2‐/‐ mice. Yet, an increase in the mean arterial pressure was seen only in the control group, from 88 ± 4 to 99 ± 3 mm Hg, with no changes in Fxyd2‐/‐ mice: 86 ± 5 vs 81 ± 9 mm Hg. Abundance of the total and cleaved (activated) forms of ENaC α‐subunit was not different between genotypes. Thus activation of NCC and NKCC2 may reflect a compensatory response to Na+ loss proximal to the cTAL and DCT in Fxyd2‐/‐ mice that appear to be in a desirable hypertension‐resistant state.