Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A family of orphan transporters has been discovered that are structurally related to the Na(+)-Cl(-)-dependent neurotransmitter transporters, including the dopamine transporter. One member of this family, the mouse XT2 gene, is predominantly expressed in the kidney and has 95% homology to rat ROSIT (renal osmotic stress-induced Na(+)-Cl(-) organic solute cotransporter). To study the physiological functions of this transporter, we generated XT2-knockout mice by gene targeting. XT2(-/-) mice develop and survive normally with no apparent abnormalities. To attempt to identify potential substrates for XT2, we screened urine from XT2-knockout mice by high-pressure liquid chromatography and mass spectrometry and found significantly elevated concentrations of glycine. To study glycine handling, XT2(+/+) and XT2(-/-) mice were injected with radiolabeled glycine, and urine samples were collected to monitor glycine excretion. After 2 h, XT2(-/-) mice were found to excrete almost twice as much glycine as the XT2(+/+) controls (P = 0.03). To determine whether the absence of the XT2 transporter affected sodium and fluid homeostasis, we measured systolic blood pressure by computerized tail-cuff manometry. Systolic blood pressure was significantly higher in XT2(-/-) mice (127 +/- 3 mmHg) than in wild-type controls (114 +/- 2 mmHg; P < 0.001). This difference in systolic blood pressure was maintained on high and low salt feeding. To examine whether the alteration in blood pressure and the defect in glycine handling were related, we measured systolic blood pressure in the XT2(-/-) mice during dietary glycine supplementation. Glycine loading caused systolic blood pressure to fall in the XT2(-/-) mice from 127 +/- 3 to 115 +/- 3 mmHg (P < 0.001), a level virtually identical to that of the wild-type controls. These data suggest that the XT2 orphan transporter is involved in glycine reabsorption and that the absence of this transporter is sufficient to cause hypertension.
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PMID:Hypertension and impaired glycine handling in mice lacking the orphan transporter XT2. 1512 38

We investigated the possible association of solute carrier family 6 member 18 (SLC6A18) with hypertension and blood pressure in Japanese, since the homologous murine XT2 gene was recently reported to be associated with hypertension. The entire coding region of SLC6A18 was sequenced in 30 unrelated Japanese subjects. The deleterious effects of the observed nonsynonymous single nucleotide polymorphisms (SNPs) on the phenotype were predicted using bioinformatics software. We tested the associations of one deleterious SNP (Y319X) with blood pressure and hypertension in a general population of 1,004 subjects in one area of Japan. Both quantitative and qualitative analyses adjusting for age and body mass index (BMI) as covariates were undertaken. Four synonymous (P7P, T32T, G37G and V387V), three missense (S12C, I32T and L478P) and one nonsense (Y319X: g1230757 C > G) polymorphisms were found. One of the synonymous polymorphisms was novel (V387V) by reference to the dbSNP database. The Y319X genotype distribution of CC:CG:GG in this population showed frequencies of 0.382, 0.461 and 0.156, respectively, which followed Hardy-Weinberg equilibrium. The nonsense polymorphism had odds ratios of 0.83 (confidence interval [CI] = 0.59-1.15, p = 0.26) in males and 0.96 (CI = 0.72-1.29, p = 0.80) in females with hypertension or current medication for hypertension. For the quantitative analysis, we excluded the current medication subgroup. The nonsense allele was not a significant predictor for systolic or diastolic blood pressure. This is the first report showing that a single polymorphism in SLC6A18 is not associated with hypertension or blood pressure in Japanese.
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PMID:A nonsense polymorphism (Y319X) of the solute carrier family 6 member 18 (SLC6A18) gene is not associated with hypertension and blood pressure in Japanese. 1634 Jan 70

The orphan transporter Slc6a18 (XT2) is highly expressed at the luminal membrane of kidney proximal tubules and displays approximately 50% identity with Slc6a19 (B(0)AT1), which is the main neutral amino acid transporter in both kidney and small intestine. As yet, the amino acid transport function of XT2 has only been experimentally supported by the urinary glycine loss observed in xt2 null mice. We report here that in Xenopus laevis oocytes, co-expressed ACE2 (angiotensin-converting enzyme 2) associates with XT2 and reveals its function as a Na(+)- and Cl(-)-de pend ent neutral amino acid transporter. In contrast to its association with ACE2 observed in Xenopus laevis oocytes, our experiments with ace2 and collectrin null mice demonstrate that in vivo it is Collectrin, a smaller homologue of ACE2, that is required for functional expression of XT2 in kidney. To assess the function of XT2 in vivo, we reanalyzed its knock-out mouse model after more than 10 generations of backcrossing into C57BL/6 background. In addition to the previously published glycinuria, we observed a urinary loss of several other amino acids, in particular beta-branched and small neutral ones. Using telemetry, we confirmed the previously described link of XT2 absence with hypertension but only in physically restrained animals. Taken together, our data indicate that the formerly orphan transporter XT2 functions as a sodium and chloride-de pend ent neutral amino acid transporter that we propose to rename B(0)AT3.
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PMID:Orphan transporter SLC6A18 is renal neutral amino acid transporter B0AT3. 1947 81