Genetic deletion of the kidney sodium/proton exchanger-3 (NHE3) does not alter calcium and phosphate balance due to compensatory responses

Søren B Poulsen; Sathish K Murali; Linto Thomas; Adrienne Assmus; Lena L Rosenbæk; Rikke Nielsen; Henrik Dimke; Timo Rieg; Robert A Fenton

doi:10.1016/j.kint.2024.07.013

Genetic deletion of the kidney sodium/proton exchanger-3 (NHE3) does not alter calcium and phosphate balance due to compensatory responses

Kidney Int. 2024 Jul 30:S0085-2538(24)00533-7. doi: 10.1016/j.kint.2024.07.013. Online ahead of print.

Authors

Søren B Poulsen¹, Sathish K Murali², Linto Thomas³, Adrienne Assmus¹, Lena L Rosenbæk¹, Rikke Nielsen¹, Henrik Dimke⁴, Timo Rieg⁵, Robert A Fenton⁶

Affiliations

¹ Department of Biomedicine, Aarhus University, Aarhus, Denmark.
² Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
³ Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA.
⁴ Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark; Department of Nephrology, Odense University Hospital, Odense, Denmark.
⁵ Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, Florida, USA; James A. Haley Veterans' Hospital, Tampa, Florida, USA. Electronic address: trieg@usf.edu.
⁶ Department of Biomedicine, Aarhus University, Aarhus, Denmark. Electronic address: robert.a.fenton@biomed.au.dk.

PMID: 39089578
DOI: 10.1016/j.kint.2024.07.013

Abstract

The sodium/proton exchanger-3 (NHE3) plays a major role in acid-base and extracellular volume regulation and is also implicated in calcium homeostasis. As calcium and phosphate balances are closely linked, we hypothesized that there was a functional link between kidney NHE3 activity, calcium, and phosphate balance. Therefore, we examined calcium and phosphate homeostasis in kidney tubule-specific NHE3 knockout mice (NHE3^loxloxPax8 mice). Compared to controls, these knockout mice were normocalcemic with no significant difference in urinary calcium excretion or parathyroid hormone levels. Thiazide-induced hypocalciuria was less pronounced in the knockout mice, in line with impaired proximal tubule calcium transport. Knockout mice had greater furosemide-induced calciuresis and distal tubule calcium transport pathways were enhanced. Despite lower levels of the sodium/phosphate cotransporters (NaPi)-2a and -2c, knockout mice had normal plasma phosphate, sodium-dependent ³²Phosphate uptake in proximal tubule membrane vesicles and urinary phosphate excretion. Intestinal phosphate uptake was unchanged. Low dietary phosphate reduced parathyroid hormone levels and increased NaPi-2a and -2c abundances in both genotypes, but NaPi-2c levels remained lower in the knockout mice. Gene expression profiling suggested proximal tubule remodeling in the knockout mice. Acutely, indirect NHE3 inhibition using the SGLT2 inhibitor empagliflozin did not affect urinary calcium and phosphate excretion. No differences in femoral bone density or architecture were detectable in the knockout mice. Thus, a role for kidney NHE3 in calcium homeostasis can be unraveled by diuretics, but NHE3 deletion in the kidneys has no major effects on overall calcium and phosphate homeostasis due, at least in part, to compensating mechanisms.

Keywords: blood pressure; calcium; gliflozins; parathyroid hormone; phosphate; proximal tubule.