Send to

Choose Destination
Physiol Rep. 2014 Dec 3;2(12). pii: e12226. doi: 10.14814/phy2.12226. Print 2014 Dec 1.

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

Author information

Laboratory of Membrane Biology, Massachusetts General Hospital, Boston, Massachusetts.
Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, California.
MGH Center for Systems Biology, Program in Membrane Biology, Massachusetts General Hospital, Boston, Massachusetts.


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.


Apical Na+ transporters; blood pressure; distal tubule; phosphorylation

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center