https://scholars.lib.ntu.edu.tw/handle/123456789/504035
Title: | Generation and analysis of the thiazide-sensitive Na+-Cl- cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome | Authors: | Yang S. Lo Y. Yu I. SHU-WHA LIN Chang T. Hsu Y. Chao T. Sytwu H. Uchida S. Sasaki S. Lin S. |
Issue Date: | 2010 | Journal Volume: | 31 | Journal Issue: | 12 | Start page/Pages: | 1304_1315 | Source: | Human Mutation | Abstract: | Gitelman syndrome (GS) is characterized by salt-losing hypotension, hypomagnesemia, hypokalemic metabolic alkalosis, and hypocalciuria. To better model human GS caused by a specific mutation in the thiazide-sensitive Na+-Cl- cotransporter (NCC) gene SLC12A3, we generated a nonsense Ncc Ser707X knockin mouse corresponding to human p.Ser710X (c.2135C>A), a recurrent mutation with severe phenotypes in Chinese GS patients. Compared with wild-type or heterozygous littermates, homozygous (Hom) knockin mice fully recapitulated the phenotype of human GS. The markedly reduced Ncc mRNA and virtually absent Ncc protein expression in kidneys of Hom mice was primarily due to nonsense-mediated mRNA decay (NMD) surveillance mechanisms. Expression of epithelial Na+ channel (Enac), Ca2+ channels (Trpv5 and Trpv6), and K+ channels (Romk1 and maxi-K) were significantly increased. Late distal convoluted tubules (DCT) volume was increased and DCT cell ultrastructure appeared intact. High K+ intake could not correct hypokalemia but caused a further increase in maxi-K but not Romk1 expression. Renal tissue from a patient with GS also showed the enhanced TRPV5 and ROMK1 expression in distal tubules. We suggest that the upregulation of TRPV5/6 and of ROMK1 and Maxi-K may contribute to hypocalciuria and hypokalemia in Ncc Ser707X knockin mice and human GS, respectively. ? 2010 Wiley-Liss, Inc. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/504035 | ISSN: | 1059-7794 | DOI: | 10.1002/humu.21364 | SDG/Keyword: | epithelial sodium channel; hydrochlorothiazide; messenger RNA; potassium channel; sodium chloride cotransporter; vanilloid receptor 5; vanilloid receptor 6; animal experiment; animal model; animal tissue; article; Chinese; controlled study; drug response; gene targeting; Gitelman syndrome; heterozygote; homozygosity; human; human tissue; hypocalciuria; hypokalemia; kidney distal tubule; mouse; nonhuman; nonsense mutation; potassium intake; priority journal; protein expression; wild type; Animals; Base Sequence; Calcium Channels; Cell Size; Codon, Nonsense; Diet; Disease Models, Animal; Female; Fluorescent Antibody Technique; Gene Knock-In Techniques; Gitelman Syndrome; Humans; Kidney; Male; Mice; Middle Aged; Molecular Sequence Data; Phenotype; Potassium Chloride; Receptors, Drug; RNA Stability; Serine; Sodium; Symporters; Thiazides; Young Adult; Mus |
Appears in Collections: | 醫學檢驗暨生物技術學系 |
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