Inhibition of Na+/H+ exchanger‐3 (NHE3) results in hyperphosphatemia without major alterations in Ca2+ homeostasis

Pharmacological and genetic inhibition of renal Na+/H+ exchanger‐3 (NHE3) may lower blood pressure in hypertensive mouse models, but potential side effects are not well‐characterized. NHE3 is proposed to play a major role in renal Ca2+ reabsorption, which is regulated by the parathyroid hormone (PTH). Furthermore, PTH also regulates phosphate (Pi) balance. Therefore, the aims of this study were to examine the effects of NHE3 inhibition on Pi and Ca2+ homeostasis. Mice with NHE3 deletion in the kidney tubule (NHE3loxloxPax8) were used to assess chronic effects, whereas mice administered the NHE3 inhibitor S3226 were used to examine acute effects. NHE3loxloxPax8 mice had increased plasma Pi and PTH levels that coincided with reduced abundances of the Na+‐Pi cotransporters (NaPi) ‐2a and ‐2c, but urinary Pi excretion was normal. Feeding mice a low Pi diet reduced PTH and increased both NaPi‐2a and ‐2c protein abundances in NHE3loxloxPax8 and control mice, but NaPi‐2c levels remained lower in NHE3loxloxPax8 mice. NHE3loxloxPax8mice were normocalcemic with normal urinary Ca2+ excretion, but had greater furosemide‐induced calciuresis, suggesting increased Na+‐K+‐Cl‐ cotransporter (NKCC2) activity. NHE3loxloxPax8 mice had reduced calciuresis subsequent to a thiazide diuretic. Treatment of wild‐type mice with the NHE3 inhibitor S3226 reduced creatinine clearance, increased plasma Pi and fibroblast growth factor 23 (FGF‐23) and reduced the abundances of NaPi‐2a and ‐2c. Plasma Ca2+ was not significantly altered by S3226 whereas urine Ca2+ excretion was transiently reduced. Collectively, inhibition of NHE3 results in hyperphosphatemia without major alterations in Ca2+ homeostasis. Data suggest that NHE3 inhibitors may constitute significant health risks due to alterations in renal function and Pi homeostasis.