Frick KK, Asplin JR, Favus MJ, Culbertson C, Krieger NS, Bushinsky DA. Increased biological response to 1,25(OH)2D3 in genetic hypercalciuric stone-forming rats. Am J Physiol Renal Physiol 304: F718-F726, 2013. First published January 23, 2013 doi:10.1152/ajprenal.00645.2012.-Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (U) calcium (Ca) excretion, have increased intestinal Ca absorption and bone Ca resorption and reduced renal Ca reabsorption, leading to increased UCa compared with the Sprague-Dawley (SD) rats. GHS rats have increased vitamin D receptors (VDR) at each of these sites, with normal levels of 1,25(OH)2D3 (1,25D), indicating that their VDR is undersaturated with 1,25D. We tested the hypothesis that 1,25D would induce a greater increase in UCa in GHS rats by feeding both strains ample Ca and injecting 1,25D (25 ng · 100 g body wt Ϫ1 · day Ϫ1 ) or vehicle for 16 days. With 1,25D, UCa in SD increased from 1.7 Ϯ 0.3 mg/day to 24.4 Ϯ 1.2 (⌬ ϭ 22.4 Ϯ 1.5) and increased more in GHS from 10.5 Ϯ 0.7 to 41.9 Ϯ 0.7 (⌬ ϭ 29.8 Ϯ 1.8; P ϭ 0.003). To determine the mechanism of the greater increase in UCa in GHS rats, we measured kidney RNA expression of components of renal Ca transport. Expression of transient receptor potential vanilloid (TRPV)5 and calbindin D28K were increased similarly in SD ϩ 1,25D and GHS ϩ 1,25D. The Na ϩ /Ca 2ϩ exchanger (NCX1) was increased in GHS ϩ 1,25D. Klotho was decreased in SD ϩ 1,25D and GHS ϩ 1,25D. TRPV6 was increased in SD ϩ 1,25D and increased further in GHS ϩ 1,25D. Claudin 14, 16, and 19, Na/K/2Cl transporter (NKCC2), and secretory K channel (ROMK) did not differ between SD ϩ 1,25D and GHS ϩ 1,25D. Increased UCa with 1,25D in GHS exceeded that of SD, indicating that the increased VDR in GHS induces a greater biological response. This increase in UCa, which must come from the intestine and/or bone, must exceed any effect of 1,25D on TRPV6 or NCX1-mediated renal Ca reabsorption. vitamin D; calcium; kidney stones; reabsorption HYPERCALCIURIA IS THE MOST common metabolic abnormality in patients with nephrolithiasis(19). Hypercalciuria leads to increased urine (U) supersaturation (SS) with respect to the solid phases of calcium hydrogen phosphate (CaHPO 4 , brushite) and calcium oxalate (CaOx), enhancing the probability of nucleation and growth of crystals into clinically significant stones (19). In humans, idiopathic hypercalciuria (IH) is characterized by increased intestinal calcium (Ca) absorption and/or decreased renal tubule Ca reabsorption resulting in hypercalciuria with normal serum (S) Ca, normal or elevated S1,25(OH) 2 D 3 (1,25D), normal S parathyroid hormone (PTH), normal or low S phosphate (P), and low bone mass (19,70,85). The familial pattern of IH is consistent with a polygenic mode of inheritance (70,71,85).To study the pathophysiology of hypercalciuria and stone formation, we have established a strain of hypercalciuric rats by selectively inbreeding Sprague-Dawley (SD) rats for increased UCa excretion (3-5, 16 -18, 20 -25, 27-29, 31, 3...