1,25(OH)₂D₃-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet.
The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 ± 0.1 to 9.3 ± 0.9 mg/day and increased more in GHS from 4.7 ± 0.3 to 21.5 ± 0.9 mg/day (P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption.
Univ. of Rochester School of Medicine and Dentistry, Div. of Nephrology, Dept. of Medicine, 601 Elmwood Ave., Box 675, Rochester, NY 14642. Kevin_Frick@URMC.Rochester.edu.
Kevin K
KK
Frick
John R
JR
Asplin
Nancy S
NS
Krieger
Christopher D
CD
Culbertson
Daniel M
DM
Asplin
David A
DA
Bushinsky
D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage*; D002118:Calcium / Q000008:administration & dosage / Q000652:urine*; D002136:Calcium, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D006934:Hypercalcemia / Q000151:congenital / Q000235:genetics / Q000378:metabolism; D053565:Hypercalciuria / Q000139:chemically induced / Q000378:metabolism*; D007408:Intestinal Absorption / Q000502:physiology; D007669:Kidney Calculi / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism*
D002136:Calcium, Dietary; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium
calcium; intestinal absorption; kidney stones; vitamin D