Critical role of the epithelial Ca2+ channel TRPV5 in active Ca2+ reabsorption as revealed by TRPV5/calbindin-D28K knockout mice.
The epithelial Ca(2+) channel TRPV5 facilitates apical Ca(2+) entry during active Ca(2+) reabsorption in the distal convoluted tubule. In this process, cytosolic Ca(2+) remains at low nontoxic concentrations because the Ca(2+) influx is buffered rapidly by calbindin-D(28K). Subsequently, Ca(2+) that is bound to calbindin-D(28K) is shuttled toward the basolateral Ca(2+) extrusion systems. For addressing the in vivo role of TRPV5 and calbindin-D(28K) in the maintenance of the Ca(2+) balance, single- and double-knockout mice of TRPV5 and calbindin-D(28K) (TRPV5(-/-), calbindin-D(28K)(-/-), and TRPV5(-/-)/calbindin-D(28K)(-/-)) were characterized. These mice strains were fed two Ca(2+) diets (0.02 and 2% wt/wt) to investigate the influence of dietary Ca(2+) content on the Ca(2+) balance. Urine analysis indicated that TRPV5(-/-)/calbindin-D(28K)(-/-) mice exhibit on both diets hypercalciuria compared with wild-type mice. Ca(2+) excretion in TRPV5(-/-)/calbindin-D(28K)(-/-) mice was not significantly different from TRPV5(-/-) mice, whereas calbindin-D(28K)(-/-) mice did not show hypercalciuria. The similarity between TRPV5(-/-)/calbindin-D(28K)(-/-) and TRPV5(-/-) mice was supported further by an equivalent increase in renal calbindin-D(9K) expression and in intestinal Ca(2+) hyperabsorption as a result of upregulation of calbindin-D(9K) and TRPV6 expression in the duodenum. Elevated serum parathyroid hormone and 1,25-dihydroxyvitamin D(3) levels accompanied the enhanced expression of the Ca(2+) transporters. Intestinal Ca(2+) absorption and expression of calbindin-D(9K) and TRPV6, as well as serum parameters of the calbindin-D(28K)(-/-) mice, did not differ from those of wild-type mice. These results underline the gatekeeper function of TRPV5 being the rate-limiting step in active Ca(2+) reabsorption, unlike calbindin-D(28K), which possibly is compensated by calbindin-D(9K).
Gkika
Dimitra
D
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Hsu
Yu-Juei
YJ
van der Kemp
Annemiete W
AW
Christakos
Sylvia
S
Bindels
René J
RJ
Hoenderop
Joost G
JG
D000042:Absorption; D000818:Animals; D064092:Calbindin 1; D064026:Calbindins; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D064030:S100 Calcium Binding Protein G / Q000235:genetics*; D050916:TRPV Cation Channels / Q000235:genetics / Q000502:physiology*
C576499:Calb1 protein, mouse; D064092:Calbindin 1; D064026:Calbindins; D015220:Calcium Channels; D064030:S100 Calcium Binding Protein G; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; D002118:Calcium