Showing SLC12A3 — NCC is a alias.
Solute carrier family 12 member 3 · UniProt P55017
SLC12A3 encodes the thiazide-sensitive Na-Cl cotransporter (NCC), a kidney-specific 12-transmembrane protein that mediates electroneutral NaCl reabsorption at the apical membrane of the distal convoluted tubule (DCT) (PMID:8812482). NCC activity is governed by N-terminal phosphorylation (Thr53/58/60, Ser71), which both promotes transport and stabilizes the protein at the apical membrane; the T58M/T60 mutation abolishing SPAK/OSR1 phosphorylation reduces NCC abundance, causes cytosolic mislocalization, and produces a Gitelman phenotype, while phosphorylation-defective NCC corrects the hypertension of WNK4-PHAII mice (PMID:23833262). This phosphorylation is set by a WNK-SPAK/OSR1 kinase cascade integrated to plasma K+: raising plasma K+ alone is sufficient to dephosphorylate and inhibit NCC (PMID:24598799, PMID:29371419), with Kir4.1-dependent DCT cells clustering WNK4 and SPAK/OSR1 into WNK bodies during K+ deficiency to drive activation (PMID:31736353). SPAK is the principal but not exclusive activating kinase, requires Cab39/Cab39l scaffolds for apical co-localization with NCC, and is regulated by multiple upstream inputs including SGK1 and aldosterone (independent of the mineralocorticoid receptor in DCT), vasopressin via AC6, calcium-sensing receptor via WNK4, α1-adrenergic/norepinephrine signaling, and PI3K/Akt (PMID:22949526, PMID:23123217, PMID:23739593, PMID:25651563, PMID:26898302, PMID:29848507, PMID:31608673, PMID:38258567). Kidney-specific WNK1 negatively tunes the cascade by targeting WNK4 and L-WNK1 for degradation (PMID:21131289, PMID:38961847). NCC abundance is independently controlled by ubiquitylation through NEDD4-2 and cullin E3 ligases, which mediate dietary salt, Mg2+, and K+ effects on the transporter (PMID:31364380, PMID:33818128, PMID:36160843, PMID:35011657). In the late DCT, NCC physically associates with ENaC subunits to coordinate distal sodium transport, an interaction enhanced by aldosterone and SGK1 (PMID:27422782, PMID:28646163). Loss-of-function mutations in SLC12A3 cause Gitelman syndrome through nonsense-mediated decay, aberrant/pseudoexon splicing, trafficking defects, or impaired intrinsic transport, with gene correction in patient iPSC-derived organoids confirming causality (PMID:17329572, PMID:20848653, PMID:22009145, PMID:25060058, PMID:34860177, PMID:36769335, PMID:21051746).
Established the molecular identity of the renal thiazide target: what gene mediates DCT NaCl reabsorption and confers thiazide sensitivity.
Evidence cDNA cloning, heterologous expression, and FISH of human SLC12A3
Defined how SLC12A3 mutations cause Gitelman syndrome by resolving distinct molecular failure modes rather than a single defect.
Evidence cDNA/transcript analysis, NMD assays, and Xenopus oocyte transport assays of patient mutants
Connected NCC phosphorylation to physiological salt handling and identified SGK1 as a required regulator of NCC phospho-activation under salt restriction.
Evidence SGK1 knockout mice with phospho-specific NCC antibodies across dietary NaCl conditions
Dissected WNK3 isoform-specific control of NCC and separated phosphorylation-dependent transport activity from surface expression.
Evidence Xenopus oocyte reconstitution with kinase-dead WNK mutants, T58 phosphomimetic mutants, and 22Na+ uptake
Established KS-WNK1 as an in vivo negative regulator of NCC linking the cascade to blood pressure.
Evidence Reciprocal transgenic overexpression and exon-4A deletion mice with NCC localization and blood pressure readouts
Showed splicing-class mutations (recurrent nonsense and deep intronic pseudoexon) ablate NCC and revealed compensatory channel remodeling underlying Gitelman electrolyte phenotypes.
Evidence Ser707X knockin mouse with renal phenotyping; RNA-based detection of intronic pseudoexon mutations with renal biopsy IHC
Refined the functional classification of NCC missense mutants by separating no-activity, trafficking-defective, and membrane-resident-but-nonfunctional alleles.
Evidence Xenopus oocyte 22Na+ uptake and surface-expression analysis of multiple missense mutants
Identified hormonal and signaling inputs into the WNK-SPAK/OSR1-NCC axis, implicating PI3K/Akt in insulin-driven NCC activation and AC6/cAMP in vasopressin-driven phosphorylation.
Evidence SpakT243A/Osr1T185A knock-in mice with PI3K inhibitors; AC6 knockout mice with V2 agonist challenge and phospho-NCC blots
Resolved that aldosterone acutely activates NCC via SGK1/SPAK phosphorylation, and that T60 phosphorylation is mechanistically required for NCC stability and apical localization.
Evidence Aldosterone minipump studies with SPAK silencing; T58M knock-in mice with WNK4-PHAII genetic cross and localization assays
Established plasma K+ as the direct upstream signal inhibiting NCC and uncovered post-transcriptional and splicing-level layers of NCC regulation.
Evidence IV KCl infusion in rats with phospho-NCC blots; P2Y2/Ca2+/parvalbumin manipulation of NCC mRNA stability in mDCT cells; minigene ESE-disruption splicing assays
PMID:24463702 PMID:24598799 PMID:25060058
Demonstrated physical NCC-ENaC coupling in DCT2 and showed DCT NCC regulation is MR-independent, distinguishing it from collecting-duct ENaC control.
Evidence Five orthogonal interaction assays (BN-PAGE, co-IP, mammalian two-hybrid, FRET, immunogold EM); mosaic MR-deletion mouse with side-by-side cell comparison
Clarified WNK-WNK regulatory logic and additional upstream activators: KS-WNK1 acts via WNK4 autophosphorylation, and CaSR signals through WNK4 to activate NCC.
Evidence Xenopus oocyte reconstitution with WNK463 inhibitor and domain deletions, co-IP of KS-WNK1/WNK4; CaSR calcimimetic studies across oocyte, HEK293, and mouse; γENaC knockout with dietary K+ manipulation
PMID:29371419 PMID:29846116 PMID:29848507
Defined the cellular machinery (WNK bodies, Kir4.1) and additional inputs (norepinephrine/α1-adrenoceptor) and degradation routes (NEDD4-2) that integrate dietary and neural signals onto NCC.
Evidence Kir4.1 and WNK4 mouse models with WNK body immunofluorescence; α1-adrenoceptor antagonism in NE-infused rats; inducible NEDD4-2 KO with Mg2+ restriction and SPAK/OSR1 epistasis
PMID:31364380 PMID:31608673 PMID:31736353
Established NEDD4-2 and cullin E3 ligases as the abundance-control arm mediating dietary salt and K+ effects on NCC, complementing the phosphorylation arm.
Evidence Kidney-specific NEDD4-2 KO with high/low-salt diets and clearance studies; CUL3-mutant mice and MLN4924 pan-cullin inhibition in ex vivo tubules
Directly demonstrated NEDD4-2 ubiquitylation of NCC controlling membrane abundance and half-life, while showing it is dispensable for K+-induced NCC reduction, and reconfirmed transport loss for frequent disease alleles.
Evidence NEDD4-2 deletion in MDCKI cells and mice with ubiquitylation, membrane fractionation, and half-life assays; Xenopus oocyte 22Na+ uptake of six frequent missense mutants
Identified Cab39/Cab39l scaffolds as required for SPAK apical trafficking and confirmed KS-WNK1 acts by degrading WNK4/L-WNK1 to set NCC K+ sensitivity.
Evidence Cab39/Cab39l double-knockout mice with SPAK localization assays; DCT-specific KS-WNK1 knockout with dietary K+ and WNK body analysis
Confirmed at the cellular level that SLC12A3 loss is directly responsible for the disease phenotype using gene correction.
Evidence CRISPR-Cas9 correction in patient iPSCs with kidney organoid differentiation and NCC expression rescue
| Year | Finding | Method | Journal | Conf | PMIDs |
|---|---|---|---|---|---|
| 1996 | Human SLC12A3 (NCC) was cloned and shown to encode a 1021 amino acid protein with 12 transmembrane domains, expressed specifically in the kidney, and selectively inhibited by thiazide diuretics, establishing it as the renal Na-Cl cotransporter. | cDNA cloning, heterologous expression, protein sequence analysis, fluorescence in situ hybridization | Genomics | High | 8812482 |
| 2007 | SLC12A3 mutations cause Gitelman syndrome through multiple mechanisms: nonsense-mediated mRNA decay of splicing mutants, defective intrinsic transport activity, and absent cell surface expression (trafficking defects), demonstrating functional classes of NCC mutants. | cDNA analysis, transcript quantification, heterologous expression in Xenopus laevis oocytes, functional transport assays | Journal of the American Society of Nephrology : JASN | High | 17329572 |
| 2009 | NCC expression and phosphorylation at Thr53, Thr58, and Ser71 are increased by dietary NaCl restriction in vivo, and this response requires SGK1, establishing SGK1 as a regulator of NCC phosphorylation in the context of salt intake. | In vivo mouse studies with SGK1 knockout, phospho-specific antibodies, Western blot | American journal of physiology. Renal physiology | High | 19570885 |
| 2009 | The renal isoform of WNK3 increases NCC expression and activity in Xenopus oocytes via a kinase-dependent, SPAK-independent pathway, while the brain isoform decreases NCC activity in a SPAK-dependent manner; T58A and T58D NCC mutants have normal surface expression but altered transport activity, and both WNK3 isoforms and WNK4 still modulate surface expression of these mutants. | Heterologous expression in Xenopus oocytes, kinase-dead mutants, 22Na+ uptake assay | Journal of the American Society of Nephrology : JASN | High | 19470686 |
| 2010 | Kidney-specific WNK1 (KS-WNK1) is a negative regulator of NCC in vivo: overexpression reduces surface expression of total and phosphorylated NCC and lowers blood pressure, while targeted deletion of exon 4A increases NCC surface expression and phosphorylation and raises blood pressure. | Transgenic mouse overexpression and gene-targeted deletion, immunofluorescent staining, in vivo blood pressure measurement | Human molecular genetics | High | 21131289 |
| 2010 | The recurrent nonsense mutation Ser707X in NCC causes Gitelman syndrome primarily through nonsense-mediated mRNA decay, resulting in virtually absent NCC protein; loss of NCC leads to compensatory upregulation of TRPV5/6 (contributing to hypocalciuria) and ROMK1/Maxi-K channels (contributing to hypokalemia). | Knockin mouse model, RT-PCR, immunohistochemistry, renal phenotyping, electrolyte measurements | Human mutation | High | 20848653 |
| 2011 | Novel NCC missense mutations cause loss of function through distinct classes: class 2 (no transport activity, e.g., Thr392Ile), class 3 (impaired trafficking to plasma membrane, e.g., Asn442Ser, Gln1030Arg), and class 4 (impaired NaCl uptake despite reaching membrane, e.g., Glu121Asp, Pro751Leu, Ser475Cys, Tyr489His). | Heterologous expression in Xenopus laevis oocytes, 22Na+ uptake assay, surface expression analysis | European journal of human genetics : EJHG | High | 22009145 |
| 2012 | The PI3K/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice; PI3K inhibitors corrected increased NCC phosphorylation, and knock-in mutations disrupting WNK→SPAK/OSR1 signaling completely corrected NCC phosphorylation and elevated blood pressure. | Knock-in mouse models (SpakT243A and Osr1T185A), PI3K/Akt inhibitor treatment, Western blot for phosphorylated NCC/SPAK/OSR1/Akt, thiazide sensitivity assay | Hypertension (Dallas, Tex. : 1979) | High | 22949526 |
| 2012 | Vasopressin, acting through the V2 receptor and adenylyl cyclase 6 (AC6), mediates phosphorylation of NCC at Thr58 in vivo; AC6 knockout mice lack the vasopressin-induced NCC phosphorylation response. | AC6 knockout mice, DDAVP (V2 agonist) administration, phospho-specific Western blot | The American journal of pathology | High | 23123217 |
| 2013 | Aldosterone acutely stimulates NCC activity and phosphorylation (without changing total NCC or surface expression) via a pathway requiring the mineralocorticoid receptor, SGK1, and SPAK; gene silencing of SPAK abolished aldosterone's effect on NCC activity. | Rodent kidney studies, mouse DCT cell line, minipump aldosterone administration, SPAK gene silencing, phospho-specific antibodies, functional transport assay | American journal of physiology. Renal physiology | High | 23739593 |
| 2013 | SPAK-mediated phosphorylation of NCC at T60 (T58 in mouse) is required for NCC protein stability and apical membrane localization; the T58M mutation prevents SPAK/OSR1 phosphorylation, reduces total NCC protein and membrane stability, causes cytosolic mislocalization, and produces Gitelman syndrome phenotype in vivo. Crossing with WNK4 D561A/+ (PHAII) mice demonstrated that phosphorylation-defective NCC corrects the hypertensive phenotype. | Knock-in mouse model (T58M), MDCK cell expression, immunofluorescence, Western blot, genetic cross with WNK4-PHAII mice | Journal of the American Society of Nephrology : JASN | High | 23833262 |
| 2014 | Raising plasma K+ concentration by intravenous KCl infusion (without K+ ingestion) is sufficient to reduce NCC phosphorylation by ~60% and drive kaliuresis and natriuresis, establishing plasma K+ concentration as the direct signal that inhibits NCC phosphorylation and activity. | In vivo rat studies with intravenous KCl infusion, phospho-specific Western blot for NCC, SPAK, NKCC2 | American journal of physiology. Renal physiology | High | 24598799 |
| 2014 | Exonic mutations in SLC12A3 can cause Gitelman syndrome by inducing exon skipping through disruption of exonic splicing enhancer sequences; mutations p.A356V and p.M672I cause aberrant splicing in vitro, and p.M672I causes exon 16 exclusion in a patient, producing a nonfunctional NCC without transport activity. | Bioinformatics ESE scoring, minigene splicing assay, patient mRNA analysis, Xenopus oocyte functional expression | Journal of the American Society of Nephrology : JASN | High | 25060058 |
| 2015 | SPAK is an important but not exclusive mediator of low-K+ diet-induced NCC activation; SPAK knockout mice showed blunted but not completely abolished NCC phosphorylation and expression in response to low-K+ diet, indicating additional low-K+-activated kinases contribute. | SPAK knockout mice, low-K+ diet, phospho-specific Western blot and immunolocalization | American journal of physiology. Renal physiology | High | 25651563 |
| 2016 | NCC and ENaC (α- and γ-subunits) physically associate in the DCT2 as demonstrated by co-immunoprecipitation, mammalian two-hybrid direct binding assay, FRET, and immunogold EM; inhibition of NCC functionally affects ENaC activity, revealing a novel mode of coordination of distal sodium transport. | Blue native PAGE, co-immunoprecipitation, mammalian two-hybrid, FRET, immunogold electron microscopy, functional transport assay | The Biochemical journal | High | 27422782 |
| 2016 | The mineralocorticoid receptor (MR) is dispensable for NCC abundance and phosphorylation regulation in the DCT, as MR-negative DCT cells showed no difference in NCC compared to MR-positive cells side-by-side in the same kidney; MR is required for ENaC in the collecting system but not NCC in DCT. | Mosaic MR-deletion mouse model, immunofluorescence comparing MR-positive and -negative cells in same tissue | Pflugers Archiv : European journal of physiology | High | 26898302 |
| 2017 | Aldosterone promotes increased physical interaction between NCC and αENaC, and this interaction is further enhanced by co-expression of SGK1 (an aldosterone-induced kinase), revealing a mechanism by which aldosterone coordinates distal sodium transport. | Co-immunoprecipitation, electron microscopy colocalization, SGK1 co-expression experiments | Scientific reports | Medium | 28646163 |
| 2018 | Kidney-specific WNK1 (KS-WNK1) activates NCC and SPAK in Xenopus oocytes; this requires interaction with another WNK kinase (abolished by WNK-WNK interacting domain deletion and WNK inhibitor WNK463). Co-immunoprecipitation showed KS-WNK1 interacts with WNK4 and promotes WNK4 autophosphorylation at Ser335, independent of changes in intracellular Cl-. | Xenopus oocyte microinjection, 22Na+ uptake, co-immunoprecipitation, WNK inhibitor (WNK463), domain deletion mutagenesis | American journal of physiology. Renal physiology | High | 29846116 |
| 2018 | Calcium-sensing receptor (CaSR) activation increases NCC activity in a WNK4-dependent manner as shown in Xenopus oocytes; in HEK293 cells, calcimimetic R-568 stimulates SPAK phosphorylation only in presence of WNK4 and is blocked by WNK4 inhibitor WNK463; CaSR activation leads to phosphorylation of KLHL3 and WNK4 with increased WNK4 abundance; acute R-568 in mice increases NCC phosphorylation in vivo. | Xenopus oocyte 22Na+ uptake, HEK293 cell transfection, Western blot, in vivo mouse treatment with calcimimetic | Journal of the American Society of Nephrology : JASN | High | 29848507 |
| 2018 | Plasma K+ concentration is the determining factor regulating NCC activity in γENaC knockout mice; when K+ was eliminated from the diet at time of γENaC deletion, plasma K+ and NCC activity remained normal, establishing plasma K+ as the dominant upstream signal for NCC regulation. | Nephron-specific γENaC knockout mice, dietary K+ manipulation, NCC phosphorylation assays, electrolyte measurements | Journal of the American Society of Nephrology : JASN | High | 29371419 |
| 2019 | WNK bodies in DCT cells cluster WNK4 and SPAK/OSR1 to promote NCC activation during K+ deficiency; phosphorylated SPAK/OSR1 is present in WNK bodies within 12 h of dietary K+ deprivation; WNK4 is the primary active WNK in WNK bodies; Kir4.1 (basolateral K+ channel) is required for DCT cells to sense plasma K+ and form WNK bodies. | Mouse dietary manipulation, WNK4-deficient mice, kidney-specific Kir4.1 deletion mice, immunofluorescence, phospho-specific antibodies | American journal of physiology. Renal physiology | High | 31736353 |
| 2019 | Mg2+ restriction downregulates total NCC abundance through NEDD4-2; dietary Mg2+ restriction failed to lower NCC in inducible nephron-specific NEDD4-2 knockout mice; this effect is independent of the NCC-activating kinases SPAK/OSR1. | Dietary manipulation, inducible nephron-specific NEDD4-2 knockout mice, SPAK/OSR1 double-knockout mice, Western blot | American journal of physiology. Renal physiology | High | 31364380 |
| 2019 | Norepinephrine (NE) activates NCC in rats through an α1-adrenoceptor-gated WNK/SPAK/OxSR1 signaling pathway; α1-adrenoceptor antagonism (but not β-adrenoceptor antagonism) restored dietary Na+-evoked NCC suppression and abolished the salt-sensitive component of hypertension. | Selective adrenoceptor antagonism in NE-infused rats, Western blot for NCC/SPAK/WNK phosphorylation, in vivo NCC activity (thiazide test), blood pressure telemetry | American journal of physiology. Renal physiology | High | 31608673 |
| 2019 | SLC12A3 (slc12a3) knockdown in zebrafish leads to structural abnormality of the kidney pronephric distal duct, demonstrating a required role in kidney tubule development. | Zebrafish slc12a3 knockdown (morpholino), morphological analysis at 1-cell stage | American journal of nephrology | Low | 25401745 |
| 2014 | P2Y2 receptor activation by ATP/UTP in mouse DCT cells triggers Ca2+ transients that destabilize NCC mRNA, reducing NCC expression; cytosolic (but not nuclear) parvalbumin overexpression abolishes ATP/UTP-induced NCC mRNA decrease, while the NCC promoter is not regulated by Ca2+ changes, demonstrating post-transcriptional regulation of NCC by cytoplasmic Ca2+. | siRNA silencing of P2Y2 receptors, cytosolic/nuclear parvalbumin overexpression, luciferase reporter, Ca2+ imaging in mDCT cells | Pflugers Archiv : European journal of physiology | High | 24463702 |
| 2021 | NEDD4-2 mediates the inhibitory effect of high-salt diet on NCC expression and phosphorylation in vivo; kidney-specific NEDD4-2 knockout mice lack high-salt-induced suppression of NCC (total and phospho-NCC), and NEDD4-2 deletion also abolishes high-salt effects on Kir4.1 and ENaC. | Kidney-specific NEDD4-2 knockout mice, high-salt/low-salt diets, Western blot, patch-clamp electrophysiology, renal clearance experiments | American journal of physiology. Renal physiology | High | 33818128 |
| 2022 | NEDD4-2 ubiquitylates NCC and modulates its plasma membrane levels and protein half-life; Nedd4-2 deletion increases NCC and pNCC levels and elevates NCC plasma membrane abundance; NCC protein half-life is increased; however, Nedd4-2 is not required for K+-induced reductions in NCC abundance in ex vivo kidney tubules. | NEDD4-2 deletion in MDCKI cells, Nedd4-2 KO mice, ex vivo kidney tubule suspension, ubiquitylation assay, plasma membrane fractionation, protein half-life assay | Frontiers in physiology | High | 36160843 |
| 2021 | Cullin E3 ubiquitin ligases (Cul1, 3, 4, 5) are involved in mediating K+ effects on NCC phosphorylation and abundance; high dietary K+ effects on phosphorylated NCC are attenuated in Cul3 mutant mice; pan-cullin inhibition with MLN4924 attenuated high K+-induced decreases in NCC phosphorylation but eliminated low K+-induced increases. | CUL3-mutant (CUL3-Het/Δ9) mice, dietary K+ manipulation, MLN4924 (pan-cullin inhibitor) in ex vivo renal tubules, Western blot for neddylated cullins and phospho-NCC | Cells | High | 35011657 |
| 2024 | Cab39 (calcium-binding protein 39) proteins are required for SPAK phosphorylation and trafficking to the apical membrane with NCC; double knockout of Cab39 and Cab39l results in complete absence of NCC phosphorylation and a Gitelman-like phenotype; in Cab39-DKO mice, SPAK/OSR1 is confined to intracellular puncta rather than colocalizing with NCC at the apical membrane. | Tamoxifen-inducible NCC-driven Cab39 knockout, global Cab39l knockout, double knockout mice, low-K+ diet, Western blot, immunofluorescence, electrolyte measurements | Hypertension (Dallas, Tex. : 1979) | High | 38258567 |
| 2022 | Six frequent SLC12A3 missense mutations (T60M, L215F, D486N, N534K, Q617R, R928C) produce structurally altered NCC protein and significantly reduced thiazide-sensitive 22Na+ uptake in Xenopus oocytes, demonstrating direct loss of transport function. | Site-directed mutagenesis, Xenopus oocyte expression, 22Na+ uptake assay, I-TASSER protein structure prediction, thiazide test in patients | Endocrine connections | High | 34860177 |
| 2024 | DCT-specific deletion of KS-WNK1 increases WNK4 and long WNK1 (L-WNK1) expression and elevates NCC phosphorylation, indicating KS-WNK1 normally targets WNK4 and L-WNK1 for degradation; in the absence of KS-WNK1, NCC loses sensitivity to low plasma K+ and WNK body formation is absent in the targeted DCT segments. | DCT-specific KS-WNK1 knockout mice, dietary K+ manipulation, Western blot, immunofluorescence for WNK bodies | American journal of physiology. Renal physiology | High | 38961847 |
| 2023 | CRISPR-Cas9 correction of SLC12A3 mutations in patient-derived iPSCs rescued NCC (NCCT) mRNA and protein expression, and improved kidney organoid maturation, demonstrating that loss of SLC12A3 function is directly responsible for the disease phenotype at the cellular level. | CRISPR-Cas9 gene correction in patient iPSCs, kidney organoid differentiation, qRT-PCR, immunoblot, immunofluorescence | International journal of molecular sciences | Medium | 36769335 |
| 2010 | Deep intronic mutations in SLC12A3 (c.1670-191C>T in intron 13 and c.2548+253C>T in intron 21) create pseudoexons with premature stop codons, causing defective NCC expression (absent apical NCC in DCT); identified by RNA-based approach from leukocyte mRNA. | RT-PCR from leukocytes and urine sediments, genomic sequencing, renal biopsy immunohistochemistry | Clinical journal of the American Society of Nephrology : CJASN | Medium | 21051746 |
| Year | Title | Journal | Citations | PMID |
|---|---|---|---|---|
| 2009 | Expression and phosphorylation of the Na+-Cl- cotransporter NCC in vivo is regulated by dietary salt, potassium, and SGK1. | American journal of physiology. Renal physiology | 211 | 19570885 |
| 2007 | Transcriptional and functional analyses of SLC12A3 mutations: new clues for the pathogenesis of Gitelman syndrome. | Journal of the American Society of Nephrology : JASN | 119 | 17329572 |
| 2014 | Increasing plasma [K+] by intravenous potassium infusion reduces NCC phosphorylation and drives kaliuresis and natriuresis. | American journal of physiology. Renal physiology | 118 | 24598799 |
| 1996 | Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3). | Genomics | 101 | 8812482 |
| 2012 | Phosphatidylinositol 3-kinase/Akt signaling pathway activates the WNK-OSR1/SPAK-NCC phosphorylation cascade in hyperinsulinemic db/db mice. | Hypertension (Dallas, Tex. : 1979) | 87 | 22949526 |
| 2010 | Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models. | Human molecular genetics | 85 | 21131289 |
| 2012 | Genotype, phenotype, and follow-up in Taiwanese patients with salt-losing tubulopathy associated with SLC12A3 mutation. | The Journal of clinical endocrinology and metabolism | 71 | 22679066 |
| 2012 | Adenylyl cyclase 6 enhances NKCC2 expression and mediates vasopressin-induced phosphorylation of NKCC2 and NCC. | The American journal of pathology | 65 | 23123217 |
| 2011 | Novel NCC mutants and functional analysis in a new cohort of patients with Gitelman syndrome. | European journal of human genetics : EJHG | 65 | 22009145 |
| 2013 | The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation. | Pflugers Archiv : European journal of physiology | 58 | 24310820 |
| 2019 | Platelet-rich clots as identified by Martius Scarlet Blue staining are isodense on NCCT. | Journal of neurointerventional surgery | 56 | 30952688 |
| 2015 | SPAK-mediated NCC regulation in response to low-K+ diet. | American journal of physiology. Renal physiology | 56 | 25651563 |
| 2010 | Generation and analysis of the thiazide-sensitive Na+ -Cl- cotransporter (Ncc/Slc12a3) Ser707X knockin mouse as a model of Gitelman syndrome. | Human mutation | 55 | 20848653 |
| 2019 | WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia. | American journal of physiology. Renal physiology | 54 | 31736353 |
| 2018 | Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. | American journal of physiology. Renal physiology | 53 | 29846116 |
| 2010 | Recurrent deep intronic mutations in the SLC12A3 gene responsible for Gitelman's syndrome. | Clinical journal of the American Society of Nephrology : CJASN | 50 | 21051746 |
| 2016 | The mineralocorticoid receptor (MR) regulates ENaC but not NCC in mice with random MR deletion. | Pflugers Archiv : European journal of physiology | 49 | 26898302 |
| 2010 | Hypertension, dietary salt intake, and the role of the thiazide-sensitive sodium chloride transporter NCCT. | Cardiovascular therapeutics | 47 | 21167012 |
| 2020 | Establishment and characterization of NCC-CDS2-C1: a novel patient-derived cell line of CIC-DUX4 sarcoma. | Human cell | 46 | 31898195 |
| 2013 | Aldosterone acutely stimulates NCC activity via a SPAK-mediated pathway. | American journal of physiology. Renal physiology | 46 | 23739593 |
| 2009 | Renal and brain isoforms of WNK3 have opposite effects on NCCT expression. | Journal of the American Society of Nephrology : JASN | 45 | 19470686 |
| 2004 | A new mutation (intron 9 +1 G>T) in the SLC12A3 gene is linked to Gitelman syndrome in Gypsies. | Kidney international | 44 | 14675033 |
| 2001 | Regulation of the sodium transporters NHE3, NKCC2 and NCC in the kidney. | Current opinion in nephrology and hypertension | 44 | 11496061 |
| 2013 | Phosphorylation regulates NCC stability and transporter activity in vivo. | Journal of the American Society of Nephrology : JASN | 43 | 23833262 |
| 2020 | Regulatory control of the Na-Cl co-transporter NCC and its therapeutic potential for hypertension. | Acta pharmaceutica Sinica. B | 42 | 34094823 |
| 2012 | Construction of nanometer cisplatin core-ferritin (NCC-F) and proteomic analysis of gastric cancer cell apoptosis induced with cisplatin released from the NCC-F. | Journal of proteomics | 41 | 22480910 |
| 2014 | Exonic mutations in the SLC12A3 gene cause exon skipping and premature termination in Gitelman syndrome. | Journal of the American Society of Nephrology : JASN | 39 | 25060058 |
| 2018 | The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. | Journal of the American Society of Nephrology : JASN | 38 | 29848507 |
| 2016 | The sodium chloride cotransporter (NCC) and epithelial sodium channel (ENaC) associate. | The Biochemical journal | 38 | 27422782 |
| 2015 | Mutations in SLC12A3 and CLCNKB and Their Correlation with Clinical Phenotype in Patients with Gitelman and Gitelman-like Syndrome. | Journal of Korean medical science | 37 | 26770037 |
| 2008 | Novel SLC12A3 mutations in Chinese patients with Gitelman's syndrome. | Nephron. Physiology | 36 | 18287808 |
| 2002 | Novel NCCT gene mutations as a cause of Gitelman's syndrome and a systematic review of mutant and polymorphic NCCT alleles. | Kidney & blood pressure research | 34 | 12590198 |
| 2008 | Chronic candesartan alters expression and activity of NKCC2, NCC, and ENaC in the obese Zucker rat. | American journal of physiology. Renal physiology | 30 | 18305093 |
| 2009 | A deep intronic mutation in the SLC12A3 gene leads to Gitelman syndrome. | Pediatric research | 29 | 19668106 |
| 2015 | Circadian exosomal expression of renal thiazide-sensitive NaCl cotransporter (NCC) and prostasin in healthy individuals. | Proteomics. Clinical applications | 28 | 25931204 |
| 2018 | Plasma Potassium Determines NCC Abundance in Adult Kidney-Specific γENaC Knockout. | Journal of the American Society of Nephrology : JASN | 27 | 29371419 |
| 2020 | WNK-SPAK/OSR1-NCC kinase signaling pathway as a novel target for the treatment of salt-sensitive hypertension. | Acta pharmacologica Sinica | 26 | 32724175 |
| 2019 | Genetic Analysis of SLC12A3 Gene in Chinese Patients with Gitelman Syndrome. | Medical science monitor : international medical journal of experimental and clinical research | 26 | 31398183 |
| 2017 | Acquired Gitelman syndrome in a primary Sjögren syndrome patient with a SLC12A3 heterozygous mutation: A case report and literature review. | Nephrology (Carlton, Vic.) | 26 | 28685938 |
| 2020 | Sympathetic Regulation of the NCC (Sodium Chloride Cotransporter) in Dahl Salt-Sensitive Hypertension. | Hypertension (Dallas, Tex. : 1979) | 25 | 32981364 |
| 2019 | The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway. | Journal of human hypertension | 25 | 30723251 |
| 2004 | Molecular characterization of the nonspecific cytotoxic cell receptor (NCCRP-1) demonstrates gilthead seabream NCC heterogeneity. | Developmental and comparative immunology | 25 | 15784294 |
| 2019 | Sympathetic regulation of NCC in norepinephrine-evoked salt-sensitive hypertension in Sprague-Dawley rats. | American journal of physiology. Renal physiology | 24 | 31608673 |
| 2018 | Elevated FGF23 Levels in Mice Lacking the Thiazide-Sensitive NaCl cotransporter (NCC). | Scientific reports | 22 | 29483574 |
| 2017 | Aldosterone Modulates the Association between NCC and ENaC. | Scientific reports | 22 | 28646163 |
| 2019 | Digenetic inheritance of SLC12A3 and CLCNKB genes in a Chinese girl with Gitelman syndrome. | BMC pediatrics | 20 | 30999883 |
| 2019 | Mg2+ restriction downregulates NCC through NEDD4-2 and prevents its activation by hypokalemia. | American journal of physiology. Renal physiology | 20 | 31364380 |
| 2014 | Genetic and biological effects of sodium-chloride cotransporter (SLC12A3) in diabetic nephropathy. | American journal of nephrology | 20 | 25401745 |
| 2011 | Exploring the intricate regulatory network controlling the thiazide-sensitive NaCl cotransporter (NCC). | Pflugers Archiv : European journal of physiology | 20 | 21927811 |
| 2021 | Deletion of renal Nedd4-2 abolishes the effect of high sodium intake (HS) on Kir4.1, ENaC, and NCC and causes hypokalemia during high HS. | American journal of physiology. Renal physiology | 19 | 33818128 |
| 2015 | A novel SLC12A3 gene homozygous mutation of Gitelman syndrome in an Asian pedigree and literature review. | Journal of endocrinological investigation | 19 | 26260218 |
| 2018 | Complicated Gitelman syndrome and autoimmune thyroid disease: a case report with a new homozygous mutation in the SLC12A3 gene and literature review. | BMC endocrine disorders | 18 | 30409157 |
| 2016 | Association of rs11643718 SLC12A3 and rs741301 ELMO1 Variants with Diabetic Nephropathy in South Indian Population. | Annals of human genetics | 18 | 27699784 |
| 2015 | Identification of two novel mutations in SLC12A3 gene in two Chinese pedigrees with Gitelman syndrome and review of literature. | Clinical endocrinology | 18 | 25990047 |
| 2023 | NCC regulation by WNK signal cascade. | Frontiers in physiology | 17 | 36685207 |
| 2021 | Potassium Effects on NCC Are Attenuated during Inhibition of Cullin E3-Ubiquitin Ligases. | Cells | 17 | 35011657 |
| 2013 | Molecular insights from dysregulation of the thiazide-sensitive WNK/SPAK/NCC pathway in the kidney: Gordon syndrome and thiazide-induced hyponatraemia. | Clinical and experimental pharmacology & physiology | 17 | 23683032 |
| 2024 | Renal upregulation of NCC counteracts empagliflozin-mediated NHE3 inhibition in normotensive but not in hypertensive male rat. | American journal of physiology. Cell physiology | 14 | 38557357 |
| 2022 | Genetic and Biological Effects of SLC12A3, a Sodium-Chloride Cotransporter, in Gitelman Syndrome and Diabetic Kidney Disease. | Frontiers in genetics | 14 | 35591852 |
| 2021 | Establishment and characterization of the NCC-GCTB4-C1 cell line: a novel patient-derived cell line from giant cell tumor of bone. | Human cell | 14 | 34731453 |
| 2020 | Establishment and characterization of NCC-GCTB1-C1: a novel patient-derived cancer cell line of giant cell tumor of bone. | Human cell | 14 | 32815117 |
| 2017 | Arg913Gln of SLC12A3 gene promotes development and progression of end-stage renal disease in Chinese type 2 diabetes mellitus. | Molecular and cellular biochemistry | 14 | 28744814 |
| 2018 | Establishment of novel patient-derived models of dermatofibrosarcoma protuberans: two cell lines, NCC-DFSP1-C1 and NCC-DFSP2-C1. | In vitro cellular & developmental biology. Animal | 13 | 30411273 |
| 2014 | A labor- and cost-effective non-optical semiconductor (Ion Torrent) next-generation sequencing of the SLC12A3 and CLCNKA/B genes in Gitelman's syndrome patients. | Journal of human genetics | 13 | 24830959 |
| 2008 | Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman's syndrome. | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 13 | 18469313 |
| 2006 | A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension. | American journal of kidney diseases : the official journal of the National Kidney Foundation | 13 | 17059986 |
| 2024 | Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC. | Hypertension (Dallas, Tex. : 1979) | 12 | 38258567 |
| 2019 | Establishment and characterization of a novel cell line, NCC-MFS1-C1, derived from a patient with myxofibrosarcoma. | Human cell | 12 | 30737712 |
| 2023 | CRISPR-Cas9-Mediated Correction of SLC12A3 Gene Mutation Rescues the Gitelman's Disease Phenotype in a Patient-Derived Kidney Organoid System. | International journal of molecular sciences | 11 | 36769335 |
| 2019 | Structure-function relationships in the renal NaCl cotransporter (NCC). | Current topics in membranes | 11 | 31196605 |
| 2019 | Arg913Gln variation of SLC12A3 gene is associated with diabetic nephropathy in type 2 diabetes and Gitelman syndrome: a systematic review. | BMC nephrology | 11 | 31660880 |
| 2018 | Establishment and characterization of the NCC-SS1-C1 synovial sarcoma cell line. | Human cell | 11 | 29450702 |
| 2022 | Establishment and characterization of NCC-GCTB5-C1: a novel cell line of giant cell tumor of bone. | Human cell | 10 | 35653034 |
| 2021 | Simultaneous Homozygous Mutations in SLC12A3 and CLCNKB in an Inbred Chinese Pedigree. | Genes | 10 | 33807568 |
| 2021 | Establishment and characterization of NCC-MFS3-C1: a novel patient-derived cell line of myxofibrosarcoma. | Human cell | 10 | 33990915 |
| 2020 | Establishment and characterization of NCC-MFS2-C1: a novel patient-derived cancer cell line of myxofibrosarcoma. | Human cell | 10 | 32870449 |
| 2019 | microRNA-1 Regulates NCC Migration and Differentiation by Targeting sec63. | International journal of biological sciences | 10 | 31754327 |
| 2023 | Minigene splicing assays reveal new insights into exonic variants of the SLC12A3 gene in Gitelman syndrome. | Molecular genetics & genomic medicine | 9 | 36597580 |
| 2022 | The E3 ubiquitin-protein ligase Nedd4-2 regulates the sodium chloride cotransporter NCC but is not required for a potassium-induced reduction of NCC expression. | Frontiers in physiology | 9 | 36160843 |
| 2021 | Establishment and characterization of NCC-DDLPS3-C1: a novel patient-derived cell line of dedifferentiated liposarcoma. | Human cell | 9 | 33677797 |
| 2021 | Establishment and characterization of NCC-MFS4-C1: a novel patient-derived cell line of myxofibrosarcoma. | Human cell | 9 | 34383271 |
| 2018 | A case of hypokalemia and proteinuria with a new mutation in the SLC12A3 Gene. | BMC nephrology | 9 | 30340552 |
| 2007 | Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes. | DNA sequence : the journal of DNA sequencing and mapping | 9 | 17654016 |
| 2024 | Sex differences in dietary sodium evoked NCC regulation and blood pressure in male and female Sprague-Dawley, Dahl salt-resistant, and Dahl salt-sensitive rats. | American journal of physiology. Renal physiology | 8 | 38813592 |
| 2022 | Frequent SLC12A3 mutations in Chinese Gitelman syndrome patients: structure and function disorder. | Endocrine connections | 8 | 34860177 |
| 2022 | Establishment and Characterization of NCC-MFS5-C1: A Novel Patient-Derived Cell Line of Myxofibrosarcoma. | Cells | 8 | 35053323 |
| 2020 | Establishment and characterization of NCC-SS3-C1: a novel patient-derived cell line of synovial sarcoma. | Human cell | 8 | 32274656 |
| 2020 | Establishment and characterization of NCC-DFSP3-C1: a novel patient-derived dermatofibrosarcoma protuberans cell line. | Human cell | 8 | 32356243 |
| 2020 | Identification of compound mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome exhibiting Bartter syndrome-liked phenotypes. | BMC nephrology | 8 | 32758178 |
| 2019 | Establishment and characterization of a novel dedifferentiated chondrosarcoma cell line, NCC-dCS1-C1. | Human cell | 8 | 30737713 |
| 2018 | Establishment and proteomic characterization of a novel synovial sarcoma cell line, NCC-SS2-C1. | In vitro cellular & developmental biology. Animal | 8 | 29626278 |
| 2014 | P2Y2 receptor activation inhibits the expression of the sodium-chloride cotransporter NCC in distal convoluted tubule cells. | Pflugers Archiv : European journal of physiology | 8 | 24463702 |
| 2006 | Life and death of the distal nephron: WNK4 and NCC as major players. | Cell metabolism | 8 | 17084706 |
| 2020 | Establishment and characterization of a novel alveolar rhabdomyosarcoma cell line, NCC-aRMS1-C1. | Human cell | 7 | 32715445 |
| 2019 | Is renal ß-adrenergic-WNK4-NCC pathway important in salt hypertension of Dahl rats? | Physiological research | 7 | 31647304 |
| 2018 | Establishment and proteomic characterization of a novel cell line, NCC-UPS2-C1, derived from a patient with undifferentiated pleomorphic sarcoma. | In vitro cellular & developmental biology. Animal | 7 | 29359268 |
| 2024 | Deletion of KS-WNK1 promotes NCC activation by increasing WNK1/4 abundance. | American journal of physiology. Renal physiology | 6 | 38961847 |
| 2023 | Regulation of the WNK4-SPAK-NCC pathway by the calcium-sensing receptor. | Current opinion in nephrology and hypertension | 6 | 37530086 |
| 2020 | Establishment and characterization of NCC-ASPS1-C1: a novel patient-derived cell line of alveolar soft-part sarcoma. | Human cell | 6 | 32648033 |
| 2019 | Establishment and characterization of novel patient-derived extraskeletal osteosarcoma cell line NCC-ESOS1-C1. | Human cell | 6 | 31625124 |
No submissions yet.