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Critical role of vitamin D in sulfate homeostasis: regulation of the sodium-sulfate cotransporter by 1,25-dihydroxyvitamin [D.sub.3]. Am J Physiol Endocrinol Metab 287: E744-E749, 2004. First published May 27, 2004; 10.1152/ajpendo.00151.2004.--As the fourth most abundant anion in the body, sulfate plays an essential role in numerous physiological processes. One key protein involved in transcellular transport of sulfate is the sodium-sulfate cotransporter NaSi-1, and previous studies suggest that vitamin D modulates sulfate homeostasis by regulating NaSi-1 expression. In the present study, we found that, in mice lacking the vitamin D receptor (VDR), NaSi-1 expression in the kidney was reduced by 72% but intestinal NaSi-1 levels remained unchanged. In connection with these findings, urinary sulfate excretion was increased by 42% whereas serum sulfate concentration was reduced by 50% in VDR knockout mice. Moreover, levels of hepatic glutathione and skeletal sulfated proteoglycans were also reduced by 18 and 45%, respectively, in the mutant mice. Similar results were observed in VDR knockout mice after their blood ionized calcium levels and rachitic bone phenotype were normalized by dietary means, indicating that vitamin D regulation of NaSi-1 expression and sulfate metabolism is independent of its role in calcium metabolism. Treatment of wild-type mice with 1,25-dihydroxyvitamin [D.sub.3] or vitamin D analog markedly stimulated renal NaSi-1 mRNA expression. These data provide strong in vivo evidence that vitamin D plays a critical rote in sulfate homeostasis. However, the observation that serum sulfate and skeletal proteoglycan levels in normoealcemic VDR knockout mice remained low in the absence of rickets and osteomalacia suggests that the contribution of sulfate deficiency to development of rickets and osteomalacia is minimal. vitamin D receptor; sulfate

Investigates the effects of vitamin D receptor (VDR) inactivation on the expression of calbindins and calcium metabolism. Effect of VDR inactivation on expression of CaBP in intestine and kidney; Effect of age on expression of CaBP in VDR(-/-) and wild-type mice.

Prior studies from our laboratory have demonstrated that K- G to A mutations were detectable in a high percentage of carcinomas which developed in the colons of animals treated with the known colonic procarcinogen, 1,2-dimethyl-hydrazine (DMH). Moreover, in this model, the incidence of these mutations was decreased by a supplemental dietary calcium regimen which concomitantly decreased the frequency of rats with multiple tumors as well as tumor size. In an attempt to clarify the possible mechanism(s) involved in this antimutagenic effect of supplemental calcium, two groups of Sprague—Dawley rats were fed semisynthetic diets containing either 0.87 or 1.80% cakium by weight for 3 weeks, s.c. injected with 100 mg/kg of DMH and killed prior to and at various time periods (16-144 h) after injection. The colons of animals were analyzed and compared with respect to -methylguanine content in DNA, -alkylguanine-DNA alkyltransferase levels as well as cellular proliferation, as assessed by immunohistochemical staining of colonic crypts by bromodeoxyundine. In certain experiments, these parameters were also analyzed in the proximal and distal colon before and at various times after administration of DMH. The results of these experiments demonstrated that supplemental dietary calcium was not found to influence significantly -methylguanine levels, alkyltransferase levels or cellular proliferation in the entire colon or in either colonic segment before or after the acute administration of DMH. DMH did, however, differentially alter all three of these biochemical parameters in the colonic segments (distal > proximal), possibly due to a greater degree of metabolic activation in the distal colon. [ABSTRACT FROM PUBLISHER]