Abstract: TH-OR075

The Cystic Fibrosis Transmembrane Regulator (CFTR) and the Na+/H+ Exchanger NHE-2 Play Important Roles in Compensatory Salt Absorption in Kidneys of Na-Cl Cotransport (NCC) Deficient Mice

Session Information

Category: Fluid, Electrolytes, and Acid-Base

  • 703 Na+, K+, Cl- Basic

Authors

  • Soleimani, Manoocher, University of Cincinnati, Cincinnati, Ohio, United States
  • Barone, Sharon L., University of Cincinnati, Cincinnati, Ohio, United States
  • Xu, Jie, University of Cincinnati, Cincinnati, Ohio, United States
  • Brooks, Marybeth, University of Cincinnati, Cincinnati, Ohio, United States
  • Zahedi, Kamyar A., University of Cincinnati, Cincinnati, Ohio, United States
Background

Background: The ablation of the Na-Cl cotransporter NCC (Slc12a3) does not cause any significant salt wasting in mice, in part due to activation of the Cl-/HCO3- exchanger pendrin and the epithelial sodium channel ENaC. However, whether other transporters/channels contribute to compensatory salt absorption in NCC null mice remains speculative.

Methods

To better identify the compensatory salt absorptive mechanisms in NCC deficient mice RNA-Seq analysis was performed on kidney cortices of wild type, NCC KO and pendrin KO mice. Results were verified by expression studies in kidneys and complemented by functional studies in live animals.

Results

One notable transporter/channel, which was significantly upregulated in NCC KO but downregulated in pendrin KO mice was CFTR. Another transporter, which was upregulated in NCC KO mice was NHE-2.
Northern hybridizations verified enhanced expression of CFTR and NHE-2 in the kidney cortex of NCC KO mice and immunofluorescence labeling studies indicated the upregulation of CFTR and NHE-2 in the CCD and DCT, respectively.
To ascertain the role of CFTR in compensatory salt absorption in NCC KO mice, WT and NCC KO mice were placed in metabolic cages and injected twice/ day with the CFTR inhibitor GlyH-101 for 4 days. Urine volume increased by ~60% and urine sodium increased by 35% vs. baseline in response to GlyH-101 treatment (p<0.05 for both parameters). Wild type mice showed no significant increase in urine output or sodium excretion in response to GlyH. NCC KO, but not WT mice showed enhanced salt excretion in response to amiloride injection which was likely resulting from combined inhibition of NHE-2 and ENaC.

Conclusion

CFTR is upregulated in the distal nephron and plays an important role in compensatory salt absorption in NCC deficient mice. In addition, NHE-2 is activated in the distal nephron and facilitates the absorption of sodium. We propose that CFTR may facilitate the activity of the Cl-/HCO3- exchanger pendrin and ENaC in B intercalated cells and principal cells, respectively, leading to enhanced salt absorption in NCC KO mice. We further propose that NHE-2 is activated and works in tandem with pendrin to facilitate the electroneutral absorption of sodium and chloride.

Funding

  • Veterans Affairs Support