Paradoxical activation of the sodium chloride cotransporter (NCC) without hypertension in kidney deficient in a regulatory subunit of Na,K‐ATPase, FXYD2

Na,K‐ATPase generates the driving force for sodium reabsorption in the kidney. Na,K‐ATPase functional properties are regulated by small proteins belonging to the FXYD family. In kidney FXYD2 is the most abundant: it is an inhibitory subunit expressed in almost every nephron segment. Its absence should increase sodium pump activity and promote Na+ retention, however, no obvious renal phenotype was detected in mice with global deletion of FXYD2 (Arystarkhova et al. 2013). Here, increased total cortical Na,K‐ATPase activity was documented in the Fxyd2−/− mouse, without increased α1β1 subunit expression. We tested the hypothesis that adaptations occur in distal convoluted tubule (DCT), a major site of sodium adjustments. Na,K‐ATPase immunoreactivity in DCT was unchanged, and there was no DCT hypoplasia. There was a marked activation of thiazide‐sensitive sodium chloride cotransporter (NCC; Slc12a3) in DCT, predicted to increase Na+ reabsorption in this segment. Specifically, NCC total increased 30% and NCC phosphorylated at T53 and S71, associated with activation, increased 4‐6 fold. The phosphorylation of the closely related thick ascending limb (TAL) apical NKCC2 (Slc12a1) increased at least twofold. Abundance of the total and cleaved (activated) forms of ENaC α‐subunit was not different between genotypes. Nonetheless, no elevation of blood pressure was evident despite the fact that NCC and NKCC2 are in states permissive for Na+ retention. Activation of NCC and NKCC2 may reflect an intracellular linkage to elevated Na,K‐ATPase activity or a compensatory response to Na+ loss proximal to the TAL and DCT.
We discovered a substantial activation of renal NCC cotransporter in mice genetically depleted for the regulatory inhibitory subunit of Na,K‐ATPase, FXYD2. Surprisingly, no significant changes in urine output as well as elevation of blood pressure were detected suggesting compensatory adaptation elsewhere in nephron