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Last update 23 Jan 2025

NCC

Last update 23 Jan 2025

Basic Info

Synonyms

Na-Cl cotransporter, Na-Cl symporter, NCC

+ [7]

Introduction

Electroneutral sodium and chloride ion cotransporter. In kidney distal convoluted tubules, key mediator of sodium and chloride reabsorption (PubMed:21613606, PubMed:22009145). Receptor for the pro-inflammatory cytokine IL18. Contributes to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2. May act either independently of IL18R1, or in a complex with IL18R1 (By similarity).

102

Drugs associated with NCC

Amlodipine Besylate/Irbesartan/Hydrochlorothiazide

Target

AT1R x NCC x VDCCs

Mechanism

AT1R antagonists [+2]

Active Org.

WinMedica

Originator Org.

WinMedica

Active Indication

Hypertension

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date18 Feb 2019

Atorvastatin/Hydrochlorothiazide/Aspirin/Enalapril

Target

ACE x COX x HMG-CoA reductase x NCC

Mechanism

ACE inhibitors [+3]

Active Org.

Alborz Darou Pharmaceutical Co.

Originator Org.

Alborz Darou Pharmaceutical Co.

Active Indication

Cardiovascular Diseases

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date01 Feb 2018

Telmisartan/Amlodipine Besylate/Hydrochlorothiazide

Target

AT1R x NCC x VDCCs

Mechanism

AT1R antagonists [+2]

Active Org.

Nippon Boehringer Ingelheim Co., Ltd.

Originator Org.

Nippon Boehringer Ingelheim Co., Ltd.

Active Indication

Hypertension

Inactive Indication-

Drug Highest PhaseApproved

First Approval Ctry. / Loc.

First Approval Date28 Sep 2016

814

Clinical Trials associated with NCC

NCT05963568

/ Not yet recruitingPhase 3IIT

Stroke Minimization Through Additive Anti-atherosclerotic Agents in Routine Treatment II Study (SMAART II)

The overall objective of the Stroke Minimization through Additive Anti-atherosclerotic Agents in Routine Treatment II (SMAART-II) is to deploy a hybrid study design to firstly, demonstrate the efficacy of a polypill (Polycap ®) containing fixed doses of antihypertensives, a statin, and antiplatelet therapy taken as two capsules, once daily orally in reducing composite vascular risk over 24 months vs. usual care among 500 recent stroke patients encountered at 12 hospitals in Ghana. Secondly, SMAART II seeks to develop an implementation strategy for routine integration and policy adoption of this polypill for post-stroke cardiovascular risk reduction in an under-resourced system burdened by suboptimal care and outcomes.

Start Date01 Mar 2025

Sponsor / Collaborator

Northern California Institute for Research & Education

NCT06744439

/ Not yet recruitingPhase 1

An Open-label, Randomized, Fed, Single-dose, 2-sequence, 4-period, Crossover Phase I Study to Evaluate the Pharmacokinetics and the Safety After Administration of BR1015 and Co-administration of BR1015-3 and BR1015-2 in Healthy Volunteers

The purpose of this clinical trial is to evaluate the pharmacokinetics and the safety after administration of BR1015 and co-administration of BR1015-3 and BR1015-2 in healthy volunteers under fed conditions

Start Date09 Jan 2025

Sponsor / Collaborator

Boryung Corp.

NCT06744062

/ Not yet recruitingPhase 1

An Open-label, Randomized, Fed, Single-dose, 2-sequence, 4-period, Crossover Study to Evaluate the Pharmacokinetics and the Safety After Administration of BR1015 and Co-administration of BR1015-1 and BR1015-2 in Healthy Volunteers

The purpose of this clinical trial is to evaluate the pharmacokinetics and the safety after administration of BR1015 and co-administration of BR1015-1 and BR1015-2 in healthy volunteers under fed conditions

Start Date05 Jan 2025

Sponsor / Collaborator

Boryung Corp.

100 Clinical Results associated with NCC

100 Translational Medicine associated with NCC

0 Patents (Medical) associated with NCC

2,291

Literatures (Medical) associated with NCC

01 Mar 2025·European Journal of Pharmacology

Camk2n1 deficiency reduces the NaCl cotransporter activity through the CUL3/KLHL3/WNK4 complex in the kidney

Article

Author: Zhang, Zihao ; Zhang, Chong ; Zhang, Ya ; Jiang, Gengru

Calcium/calmodulin dependent protein kinase II inhibitor 1 (Camk2n1) is closely associated with a peak logarithm of odds score in quantitative trait loci for systolic blood pressure. Increased Camk2n1 mRNA expression has been specifically observed in the kidneys of hypertension mouse models. However, the precise role of Camk2n1 in the kidney remains unclear. We generated Camk2n1-/- mice using the CRISPR/Cas9 system. Compared to controls, Camk2n1-/- mice exhibited consistently lower systolic blood pressure across all measured time points. Deletion of Camk2n1 resulted in decreased apical labeling of phosphorylated and total thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule. NCC phosphorylation is regulated by activated SPAK/OSR1 kinases, which act downstream of With-No-lysine (K) kinase (WNK). In Camk2n1-/- mice, the elevated abundances of key components of the Cullin 3 (CUL3) RING ubiquitin ligase, including neddylated CUL3 and the adaptor Kelch-like protein 3, promoted proteasomal degradation of WNK4. In renal tissues, Camk2n1 deletion led to increased mRNA and protein levels of ubiquitin-like modifier-activating enzyme 3 (UBA3) and ubiquitin-conjugating enzyme E2 (UBE2M). Conversely, Camk2n1 overexpression in HEK293 cells resulted in decreased levels of UBA3 and UBE2M, along with reduced CUL3 neddylation. Treatment with MLN4924 effectively suppressed CUL3 hyperneddylation and restored WNK4 levels in the kidneys of Camk2n1-/- mice. In summary, Camk2n1 deletion lowers blood pressure, likely by promoting WNK4 degradation through dysregulated CUL3 RING ubiquitin ligase activity, which leads to decreased NCC activity.

10 Jan 2025·Medicine

Gitelman syndrome with diabetes and kidney stones: A case report

Article

Author: Ye, Xiongwei ; Wu, Huishan ; Li, Meng

Rationale:Gitelman syndrome (GS) is a rare hereditary electrolyte disorder caused by mutations in the SLC12A3 gene. There is limited literature on the role of hydrochlorothiazide (HCT) testing and the SLC12A3 single heterozygous mutation in the diagnosis and management of patients with GS. In addition, cases of GS with concomitant kidney stones are rare.Patient concerns:A 48-year-old male patient suffered from unexplained hypokalemia for >10 years.Diagnoses:The patient was diagnosed with GS, type 2 diabetes mellitus, and kidney stones.Interventions:He was given potassium chloride sustained-release tablets and potassium magnesium aspartate tablets.Outcomes:His irregular potassium supplementation and hypoglycemic therapy resulted in poor control of potassium and blood glucose levels.Lessons:When unexplained hypokalemia is observed, the HCT test can help with the diagnosis of GS. When genetic testing reveals that a patient only carries only 1 SLC12A3 mutant allele, he requires further genetic evaluation. The patient’s combination of kidney stones and cysts could not exclude the diagnosis of GS. Patients with GS and diabetes should be monitored for the development of diabetic ketoacidosis.

01 Jan 2025·European Journal of Internal Medicine

Association of non-cardiac comorbidities and sex with long-term Re-hospitalization for heart failure

Article

Author: Carluccio, Erberto ; Bandera, Francesco ; Madotto, Fabiana ; Ambrosio, Giuseppe ; Antonelli, Barbara ; Tagliabue, Elena ; Lund, Lars H ; Galati, Giuseppe ; Pontiroli, Antonio E ; Pellicori, Pierpaolo ; Leoni, Olivia

Heart failure (HF) often coexists with non-cardiac comorbidities (NCC), but their association with long-term HF re-hospitalizations is not defined. Using the Lombardy Regional Health Database, that includes >10 million residents, we assessed the risk of re-hospitalization for HF after first HF discharge as a function of NCC, employing age- and sex-adjusted Cox proportional-hazard models. Kaplan Meier curves for HF re-hospitalizations were stratified for number of NCC. End of follow-up was June 30th 2021. Between January 1st 2015 to December 31st 2019, 88,528 consecutive patients were discharged from hospital with a primary diagnosis of HF; over 42.8 ± 18.3 months follow-up, 79,533 HF re-hospitalizations occurred (32.94/100 patient/year). Number of NCC, age, and male sex were significantly associated with re-hospitalization risk. Compared to those without NCC, females and males with >4 NCC had a 3.08 (CI 2.73-3.47) and a 2.62 (CI 2.39-2.87) fold higher risk, respectively. Risk of all-cause death increased with number of NCC (hazard ratio (HR): 1.42 (1.38-1.46) for HF patients with 1-2 NCC, HR: 1.90 (1.82-1.98) for patients with 3-4 NCC, HR: 2.20 (2.01-2.40) for those with HF and >4 NCC), as it did the number of days spent in hospital because of HF (from 19.91±19.25 for patients without NCC to 45.35±33.00 days for those with >4 NCC, p < 0.0001). In conclusion, this study shows that in patients hospitalized with HF, HF re-hospitalizations, all-cause mortality, and time spent in hospital increased with number of NCC. NCC associates with a worse clinical trajectory in patients with HF.

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