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 a1b1 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 a-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.