Critical role of vitamin D in sulfate homeostasis: regulation of the sodium-sulfate cotransporter by 1,25-dihydroxyvitamin D₃

Abstract

Critical role of vitamin D in sulfate homeostasis: regulation of the sodium-sulfate cotransporter by 1,25-dihydroxyvitamin D3. 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 D3 or vitamin D analog markedly stimulated renal NaSi-1 mRNA expression. These data provide strong in vivo evidence that vitamin D plays a critical role in sulfate homeostasis. However, the observation that serum sulfate and skeletal proteoglycan levels in normocalcemic 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 INORGANIC SULFATE is the fourth most abundant anion in mammalian plasma. As such, sulfate is essential for numerous physiological functions. For instance, sulfate is involved in activation and detoxification of a variety of endogenous and exogenous substances such as xenobiotics, steroids, neurotransmitters, and bile acids (30, 31). Sulfate conjugation is essential for biosynthesis of a large number of structural proteins such as sulfated glycosaminoglycans (a major component of the cartilage), cerebroside sulfate (a constituent of the myelin membranes in the brain), and heparin sulfate (required for anticoagulation) (10,12,32). Undersulfation of cartilage proteoglycans has been linked to three types of human inherited osteochondrodysplasia disorders, which are caused by mutations in the diastrophic dysplasia sulfate transporter gene (17,18,39,40). Diastrophic dysplasia sulfate transporter protein transports extracellular sulfate into chondrocytes.In mammals, sulfate homeostasis is largely regulated by the kidney. The majority of filtered sulfate is reabsorbed in the proximal tubules, and only ϳ5-20% of the filtered load is excreted into the urine (5, 29). Transcellular trans...

Controlling Sulfuryl-Transfer Biology

“…These receptors translate the molecular information contained in the metabolome into transcriptional activities that underlie complex cellular responses to hundreds of compounds including many drugs (Meloche et al, 2002), estrogens (Falany et al, 2002), androgens (Falany and Falany, 1996), D vitamins (Bolt et al, 2004), glucocorticoids (Singer et al, 1985), and Liver-X-receptor modulators (Cook et al, 2009). Nearly half of nuclear receptors do not have well defined ligands (Kliewer et al, 1999).…”

Regulation of the Sodium/Sulfate Co-transporter by Farnesoid X Receptor α

“…In addition, the relative importance of Vdr in the maintenance of sulfate homeostasis has been established, since mice deficient in Vdr display increased sulfate excretion into the urine and a concurrent decrease in serum sulfate levels (36). The observed hyposulfatemic phenotype in the Vdr Ϫ/Ϫ mice is attributed to a decrease in the basal expression of Slc13a1 as compared with wild-type mice (36).…”

Association between a Protein Polymorphism in the Start Codon of the Vitamin D Receptor Gene and Severe Diabetic Retinopathy in C-Peptide-Negative Type 1 Diabetes

“…In molecular terms, VD can reduce nitric oxide production via inducible nitric oxide synthase down-regulation (41), inhibit vascular endothelial growth factor (VEGF) induced endothelial cell proliferation (42), down-regulate the IGF-I pathway (43), up-regulate the cellular transporters of sulfate (44) which are negative regulators of angiogenesis (45), down-regulate the renin-angiotensin system (46), stimulate the TGF␤-1 (an antiproliferative and proapoptotic molecule) (47), and inhibit multiple proinflammatory and proangiogenic cytokines (4 -6, 25-27). All of these molecules have been implicated in the pathogenesis of DR. On the other hand, calcium homeostasis and calcium-dependent signaling pathways have an important role in the development of retinal hypoxia (48), a major process in severe DR.…”