Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice
Vitamin D plays an important role in Ca(2+) homeostasis by controlling Ca(2+) (re)absorption in intestine, kidney, and bone. The epithelial Ca(2+) channel TRPV5 mediates the Ca(2+) entry step in active Ca(2+) reabsorption. TRPV5 knockout (TRPV5(-/-)) mice show impaired Ca(2+) reabsorption, hypercalciuria, hypervitaminosis D, and intestinal hyperabsorption of Ca(2+). Moreover, these mice demonstrate upregulation of intestinal TRPV6 and calbindin-D(9K) expression compared with wild-type mice. For addressing the role of the observed hypervitaminosis D in the maintenance of Ca(2+) homeostasis and the regulation of expression levels of the Ca(2+) transport proteins in kidney and intestine, TRPV5/25-hydroxyvitamin-D(3)-1alpha-hydroxylase double knockout (TRPV5(-/-)/1alpha-OHase(-/-)) mice, which show undetectable serum 1,25(OH)(2)D(3) levels, were generated. TRPV5(-/-)/1alpha-OHase(-/-) mice displayed a significant hypocalcemia compared with wild-type mice (1.10 +/- 0.02 and 2.54 +/- 0.01 mM, respectively; P < 0.05). mRNA levels of renal calbindin-D(28K) (7 +/- 2%), calbindin-D(9K) (32 +/- 4%), Na(+)/Ca(2+) exchanger (12 +/- 2%), and intestinal TRPV6 (40 +/- 8%) and calbindin-D(9K) (26 +/- 4%) expression levels were decreased compared with wild-type mice. Hyperparathyroidism and rickets were present in TRPV5(-/-)/1alpha-OHase(-/-) mice, more pronounced than observed in single TRPV5 or 1alpha-OHase knockout mice. It is interesting that a renal Ca(2+) leak, as demonstrated in TRPV5(-/-) mice, persisted in TRPV5(-/-)/1alpha-OHase(-/-) mice, but a compensatory upregulation of intestinal Ca(2+) transporters was abolished. In conclusion, the elevation of serum 1,25(OH)(2)D(3) levels in TRPV5(-/-) mice is responsible for the upregulation of intestinal Ca(2+) transporters and Ca(2+) hyperabsorption. Hypervitaminosis D, therefore, is of crucial importance to maintain normocalcemia in impaired Ca(2+) reabsorption in TRPV5(-/-) mice.
|Keywords||Animals, Biological Transport, Calcium Channels/*deficiency/genetics/*physiology, Calcium/blood/*metabolism/urine, Crosses, Genetic, Female, Homeostasis, Kidney/physiology, Male, Metabolic Diseases/*metabolism, Mice, Mice, Knockout, Polymerase Chain Reaction, TRPV Cation Channels/*deficiency/genetics/*physiology, Vitamin D/*metabolism|
|Persistent URL||dx.doi.org/10.1681/ASN.2005060632, hdl.handle.net/1765/15458|
Renkema, K.Y., Nijenhuis, T., van der Eerden, B.C.J., Kemp, A.W.C.M., Weinans, H.H., van Leeuwen, J.P.T.M., … Hoenderop, J.G.J.. (2005). Hypervitaminosis D mediates compensatory Ca2+ hyperabsorption in TRPV5 knockout mice. American Society of Nephrology. Journal, 16(11), 3188–3195. doi:10.1681/ASN.2005060632