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 acidifica-tion. Here, we investigated themechanisms 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-phos-phate 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. J Am Soc Nephrol 20: 1705–1713, 2009. doi: 10.1681/ASN.2008111195 Hypercalciuria constitutes the main risk factor i