Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 20, Issue 8, Pages 1705-1713Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2008111195
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Funding
- European Science Foundation
- Swiss National Research Foundation [31-109677/1]
- EU 6th Framework project EuReGene
- ERA-EDTA
- Dutch Kidney Foundation [C03.6017]
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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 131 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.
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