Disease relevance of Slc12a3

• Mutations in the gene encoding the thiazide-sensitive Na+-Cl- cotransporter (NCC) of the distal convoluted tubule cause Gitelman's syndrome, an inherited hypokalemic alkalosis with hypomagnesemia and hypocalciuria [1].
• Estrogen enhances whereas tamoxifen retards development of Tsc mouse liver hemangioma: a tumor related to renal angiomyolipoma and pulmonary lymphangioleiomyomatosis [2].
• We found that the Tsc mouse liver hemangioma are composed predominantly of endothelial cells but with a smooth muscle component, and express HMB45 antigen, estrogen receptor, and progesterone receptor, similar to lymphangioleiomyomatosis and angiomyolipoma [2].
• A single injection of TNP-labeled mouse gamma-globulin (TNP-IgG) can render the contact sensitivity response of mice resistant to suppressor cells (Tsc) and their biologically active cellfree products (TsF) [3].
• Germfree mice were colonized with Lactobacillus johnsonii (NCC 533) or Lactobacillus paracasei (NCC 2461) [4].

High impact information on Slc12a3

• This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT [5].
• Thiazide diuretics enhance renal Na+ excretion by blocking the Na+-Cl- cotransporter (NCC), and mutations in NCC result in Gitelman syndrome [6].
• Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6) [6].
• Mouse WNK4 was cloned and expressed in Xenopus oocytes with or without NCC [7].
• This effect did not result from defects in NCC synthesis or processing, but was associated with an 85% reduction in NCC abundance at the plasma membrane [7].

Chemical compound and disease context of Slc12a3

• NCC-deficient mice had significantly elevated plasma aldosterone levels and exhibited hypocalciuria, hypomagnesemia, and compensated alkalosis [8].

Biological context of Slc12a3

• WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis [9].
• These data indicate that the loss of NCC activity in the mouse causes only subtle perturbations of sodium and fluid volume homeostasis, but renal handling of Mg2+ and Ca2+ are altered, as observed in Gitelman's syndrome [1].
• Ion transport kinetics in all mutant clones were similar to wild-type TSC, except in G627V, in which a small but significant increase in affinity for extracellular Cl(-) was observed [10].
• Profiling of renal tubule Na+ transporter abundances in NHE3 and NCC null mice using targeted proteomics [11].
• The associated phenotypes due to loss-of-function mutations in NCC and NKCC2 are consistent, in part, with their functional roles in the distal convoluted tubule and thick ascending limb, respectively [12].

Anatomical context of Slc12a3

• Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively [9].
• Our data show that biochemical and functional properties of the mutant TSCs are similar to wild-type TSC but that the surface expression is reduced, suggesting that these mutations impair the insertion of a functional protein into the plasma membrane [10].
• We therefore propose that the present in vitro experiments (long-lasting exposure to a high concentration of ET3) mimic the environment encountered by NCC in vivo when they migrate to the skin under the ectoderm that expresses ET3 [13].
• The effect of ET3 on these two NC derivatives was confirmed by the quantitative analysis of clones derived from individual NCC subjected to ET3: we found a large increase in the survival and proliferation of unipotent and bipotent precursors for glial cells and melanocytes, with no significant effect on multipotent cells generating neurons [13].
• Lyt-1 T cells of mice treated with TNP-IgG can protect the adoptive contact sensitivity response of immune cells from the antigen-specific suppressive effect produced by the addition of antigen-specific TsF or Tsc [3].

Associations of Slc12a3 with chemical compounds

• The chimera NCC, in which Met1-Gly354 of the SR Ca(2+)-ATPase were replaced with the corresponding portion of the Na+,K(+)-ATPase, lost the thapsigargin-sensitive Ca(2+)-ATPase activity seen in CCC and [n/c]CC [14].
• Immunofluorescent detection of distal tubule marker proteins and ultrastructural analysis revealed that the early DCT, which physiologically lacks epithelial Na(+) (ENaC) and Ca(2+) (TRPV5) channels, was virtually absent in NCC-deficient mice [8].
• In addition, plasma aldosterone levels were significantly elevated in NCC (-/-) mice even in the presence of a low-potassium diet [15].
• Life and death of the distal nephron: WNK4 and NCC as major players [16].

Other interactions of Slc12a3

• We investigated the mechanism of compensation that allows maintenance of sodium balance in NHE3 knockout mice and in NCC knockout mice [11].

Analytical, diagnostic and therapeutic context of Slc12a3

• To gain a better understanding of the role of NCC in sodium and fluid volume homeostasis and in the pathogenesis of Gitelman's syndrome, we used gene targeting to prepare an NCC-deficient mouse [1].
• Western blot analysis revealed immunoreactive bands in all mutant TSCs that were undistinguishable from wild-type TSC [10].

References