Acid-base status determines the renal expression of Ca²⁺ and Mg²⁺ transport proteins

Chronic metabolic acidosis results in renal Ca²⁺ and Mg ²⁺ wasting, whereas chronic metabolic alkalosis is known to exert the reverse effects. It was hypothesized that these adaptations are mediated at least in part by the renal Ca²⁺ and Mg²⁺ transport proteins. The aim of this study, therefore, was to determine the effect of systemic acid-base status on renal expression of the epithelial Ca²⁺ channel TRPV5, the Ca²⁺-binding protein calbindin-D_28K, and the epithelial Mg²⁺ channel TRPM6 in relation to Ca²⁺ and Mg²⁺ excretion. Chronic metabolic acidosis that was induced by NH₄Cl loading or administration of the carbonic anhydrase inhibitor acetazolamide for 6 d enhanced calciuresis accompanied by decreased renal TRPV5 and calbindin-D_28K mRNA and protein abundance in wild-type mice. In contrast, metabolic acidosis did not affect Ca²⁺ excretion in TRPV5 knockout (TRPV5^-/-) mice, in which active Ca²⁺ reabsorption is effectively abolished. This demonstrates that downregulation of renal Ca²⁺ transport proteins is responsible for the hypercalciuria. Conversely, chronic metabolic alkalosis that was induced by NaHCO₃ administration for 6 d increased the expression of Ca²⁺ transport proteins accompanied by diminished urine Ca²⁺ excretion in wild-type mice. However, this Ca²⁺-sparing action persisted in TRPV5 ^-/- mice, suggesting that additional mechanisms apart from upregulation of active Ca²⁺ transport contribute to the hypocalciuria. Furthermore, chronic metabolic acidosis decreased renal TRPM6 expression, increased Mg²⁺ excretion, and decreased serum Mg ²⁺ concentration, whereas chronic metabolic alkalosis resulted in the exact opposite effects. In conclusion, these data suggest that regulation of Ca²⁺ and Mg²⁺ transport proteins contributes importantly to the effects of acid-base status on renal divalent handling.