The calcium-sensing receptor promotes urinary acidification to prevent nephrolithiasis

Hypercalciuria increases the risk for urolithiasis, but renal adaptive mechanisms reduce this risk. For example, transient receptor potential vanilloid 5 knockout (TPRV5^-/-) mice lack kidney stones despite urinary calcium (Ca²⁺) wasting and hyperphosphaturia, perhaps as a result of their significant polyuria and urinary acidification. Here, we investigated the mechanisms linking hypercalciuria with these adaptive mechanisms. Exposure of dissected mouse outer medullary collecting ducts to high (5.0 mM) extracellular Ca²⁺ stimulated H⁺-ATPase activity. In TRPV5^-/- mice, activation of the renal Ca²⁺-sensing receptor promoted H ⁺-ATPase-mediated H⁺ excretion and downregulation of aquaporin 2, leading to urinary acidification and polyuria, respectively. Gene ablation of the collecting duct-specific B1 subunit of H⁺-ATPase in TRPV5^-/- mice abolished the enhanced urinary acidification, which resulted in severe tubular precipitations of Ca²⁺-phosphate in the renal medulla. In conclusion, activation of Ca²⁺-sensing receptor by increased luminal Ca²⁺ leads to urinary acidification and polyuria. These beneficial adaptations facilitate the excretion of large amounts of soluble Ca²⁺, which is crucial to prevent the formation of kidney stones.