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 (Ca(2+)) 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 Ca(2+) stimulated H(+)-ATPase activity. In TRPV5(-/-) mice, activation of the renal Ca(2+)-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 Ca(2+)-phosphate in the renal medulla. In conclusion, activation of Ca(2+)-sensing receptor by increased luminal Ca(2+) leads to urinary acidification and polyuria. These beneficial adaptations facilitate the excretion of large amounts of soluble Ca(2+), which is crucial to prevent the formation of kidney stones.
Renkema
Kirsten Y
KY
Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
Velic
Ana
A
Dijkman
Henry B
HB
Verkaart
Sjoerd
S
van der Kemp
Annemiete W
AW
Nowik
Marta
M
Timmermans
Kim
K
Doucet
Alain
A
Wagner
Carsten A
CA
Bindels
René J
RJ
Hoenderop
Joost G
JG
D000818:Animals; D051399:Aquaporin 2 / Q000378:metabolism; D002118:Calcium / Q000652:urine; D015220:Calcium Channels / Q000235:genetics; D006863:Hydrogen-Ion Concentration; D053565:Hypercalciuria / Q000652:urine*; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000201:enzymology; D051379:Mice; D018345:Mice, Knockout; D053040:Nephrolithiasis / Q000652:urine*; D010641:Phenotype; D028061:Phosphate Transport Proteins / Q000378:metabolism; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*
C496024:Aqp2 protein, mouse; D051399:Aquaporin 2; D015220:Calcium Channels; D028061:Phosphate Transport Proteins; D044169:Receptors, Calcium-Sensing; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C480628:Atp6v1b1 protein, mouse; D025262:Vacuolar Proton-Translocating ATPases; D002118:Calcium