Role of the alternative splice variant of NCC in blood pressure control

Wardak, Hila; Tutakhel, Omar A. Z.; Wijst, Jenny van der

doi:10.1080/19336950.2018.1528820

Cited by 4 publications

(5 citation statements)

References 76 publications

(111 reference statements)

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“…NCC, encoded by the SLC12A3 gene, is expressed in the distal convoluted tubule in the kidney, responsible for sodium reabsorption and playing a pivotal role in extracellular fluid volume and blood pressure control (8)(9)(10)(11). Malfunction of NCC leads to renal Na + waste and hypotension, causing Gitelman syndrome, a widely reported inherited kidney disease, depicted by metabolic alkalosis and hypokalemia, along with urinary calcium, hypocalcemia, and hypomagnesaemia (5,12).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of the human sodium-chloride cotransporter NCC

et al. 2022

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The sodium-chloride cotransporter NCC mediates the coupled import of sodium and chloride across the plasma membrane, playing vital roles in kidney extracellular fluid volume and blood pressure control. Here, we present the full-length structure of human NCC, with 2.9 Å for the transmembrane domain and 3.8 Å for the carboxyl-terminal domain. NCC adopts an inward-open conformation and a domain-swap dimeric assembly. Conserved ion binding sites among the cation-chloride cotransporters and the Na2 site are observed in our structure. A unique His residue in the substrate pocket in NCC potentially interacts with Na1 and Cl1 and might also mediate the coordination of Na2 through a Ser residue. Putative observed water molecules are indicated to participate in the coordination of ions and TM coupling. Together with transport activity assays, our structure provides the first glimpse of NCC and defines ion binding sites, promoting drug development for hypertension targeting on NCC.

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Section: Introductionmentioning

confidence: 99%

Cryo-EM structure of the human sodium-chloride cotransporter NCC

et al. 2022

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“…The molecular cloning of the human NCC has revealed the existence of three distinct isoforms resulting from alternative splicing. Of these, isoforms NCC1 and NCC2, which consist of 1030 amino acids each, are exclusively identified in humans and higher primates (63). This specificity highlights a potential limitation in the translational applicability of findings from mDCT models to human physiology.…”

Section: Discussionmentioning

confidence: 99%

“…The molecular cloning of the human NCC has revealed the existence of three distinct isoforms resulting from alternative splicing. Of these, isoforms NCC 1 and NCC 2 , which consist of 1030 and 1029 amino acids each, are exclusively identified in humans and higher primates and functionally distinct, whereas NCC 3 with 1021 amino acids (68). The splicing variants of the NCC exhibit discrepancies in naming between the NCBI and UniProt databases.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Cell Models of the Distal Convoluted Tubule: A Systematic Review of Cell Lines, Culture Condition and Gene Expression

Zhong,

Sun,

Grillo

et al. 2024

Preprint

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This review examines the crucial role of human cellular models in renal physiology research, with a specific focus on the distal convoluted tubule (DCT). It aims to provide a comprehensive summary of the origins, culture practices, and genetic studies associated with commonly employed DCT cell models. To achieve this, a systematic literature review was performed on Europe PMC, employing a Boolean search strategy. A total of 6,559 articles were initially screened, resulting in 301 articles on human-origin cell models, 69 on murine models, and 29 on canine models being included in the final analysis. Notably, the review identified two studies that introduced novel immortalised human DCT cell lines developed from primary DCT cells. This paper provides a detailed account of the lineage of each cell model, their prevalent culture conditions, and the frequency and nature of gene transfections—both wild type and mutant—conducted in these models. A significant observation from the analysis was the inconsistent reporting of methodological details across studies, which compromises the reproducibility of the research. Additionally, there was a considerable variation in culture conditions and transfection methods used across different studies. The review also highlights that HEK293 family and murine DCT cell lines do not serve as accurate models for DCT cells, pointing out the frequent need for transfecting DCT-specific genes to simulate DCT functionality adequately.NEW & NOTEWORTHYThis review is the first review to detail the current state of play with cell models of the distal convoluted tubule, including endogenous protein expression, culture conditions etc. We expect this review to be of great utility to established and early career researchers who are interested in nephrological or hypertensive patho/physiology. We have highlighted some important gaps in reporting the established cell models, we think that this kind of review is important for open science.

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“…The Na + -Cl − co-transporter (NCC), which is encoded by the SLC12A3 gene, is the most representative thiazide-sensitive Na + -Cl− co-transporter that is expressed on the apical side of DCT [ 12 , 21 , 204 , 205 , 206 ]. NCC contributes to renal electrolyte transport by reabsorbing one sodium ion along with a chloride ion, and is ablated by thiazide diuretics.…”

Section: Wnk Interactive Channels In the Distal Convoluted Tubule (Dct)mentioning

confidence: 99%

“…The activated SPAK and OSR1 activate NCC by phosphorylating Thr46, 55, 60 (human) [ 11 , 211 ]; Ser73, 91, 126 (human) [ 11 , 145 , 215 ]; Thr48, 53, 58 (mouse and rat) [ 11 ]; and Ser71, 89, 124 (mouse and rat) [ 216 ], thereby showing that WNK has a stimulating effect on NCC. Interestingly, Thr60 was shown by several studies to be a critical regulator of NCC activity, as changing T60 to a non-phosphorylated amino acid (T60A) prevented or reduced phosphorylation at other sites (T48, T55, S73, or S91) ( Table 1 ) [ 11 , 205 , 214 , 217 ].…”

Section: Wnk Interactive Channels In the Distal Convoluted Tubule (Dct)mentioning

confidence: 99%

The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis

Lin

Chang

et al. 2022

Biomedicines

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The with-no-lysine (WNK) kinase family, comprising four serine-threonine protein kinases (WNK1-4), were first linked to hypertension due to their mutations in association with pseudohypoaldosteronism type II (PHAII). WNK kinases regulate crucial blood pressure regulators, SPAK/OSR1, to mediate the post-translational modifications (PTMs) of their downstream ion channel substrates, such as sodium chloride co-transporter (NCC), epithelial sodium chloride (ENaC), renal outer medullary potassium channel (ROMK), and Na/K/2Cl co-transporters (NKCCs). In this review, we summarize the molecular pathways dysregulating the WNKs and their downstream target renal ion transporters. We summarize each of the genetic variants of WNK kinases and the small molecule inhibitors that have been discovered to regulate blood pressure via WNK-triggered PTM cascades.

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Role of the alternative splice variant of NCC in blood pressure control

Cited by 4 publications

References 76 publications

Cryo-EM structure of the human sodium-chloride cotransporter NCC

Cryo-EM structure of the human sodium-chloride cotransporter NCC

Mammalian Cell Models of the Distal Convoluted Tubule: A Systematic Review of Cell Lines, Culture Condition and Gene Expression

The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis

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