Molecular mechanisms for the modulation of blood pressure and potassium homeostasis by the distal convoluted tubule

Castañeda‐Bueno, María; Ellison, David H.; Gamba, Gerardo

doi:10.15252/emmm.202114273

Cited by 17 publications

(17 citation statements)

References 130 publications

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“…Aldosterone is the most important hormone in the regulation of Na + homeostasis in the distal nephron. One may argue that aldosterone regulates Na + homeostasis directly in the connecting tubule and the CD, and indirectly in DCT [40]. However, due to the technical difficulty, the role of aldosterone in DCT may have been underestimated [41].…”

Section: Plos Onementioning

confidence: 99%

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

et al. 2022

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HIV-associated nephropathy (HIVAN) impairs functions of both glomeruli and tubules. Attention has been previously focused on the HIVAN glomerulopathy. Tubular injury has drawn increased attention because sodium wasting is common in hospitalized HIV/AIDS patients. We used viral protein R (Vpr)-transgenic mice to investigate the mechanisms whereby Vpr contributes to urinary sodium wasting. In phosphoenolpyruvate carboxykinase promoter-driven Vpr-transgenic mice, in situ hybridization showed that Vpr mRNA was expressed in all nephron segments, including the distal convoluted tubule. Vpr-transgenic mice, compared with wild-type littermates, markedly increased urinary sodium excretion, despite similar plasma renin activity and aldosterone levels. Kidneys from Vpr-transgenic mice also markedly reduced protein abundance of the Na+-Cl- cotransporter (NCC), while mineralocorticoid receptor (MR) protein expression level was unchanged. In African green monkey kidney cells, Vpr abrogated the aldosterone-mediated stimulation of MR transcriptional activity. Gene expression of Slc12a3 (NCC) in Vpr-transgenic mice was significantly lower compared with wild-type mice, assessed by both qRT-PCR and RNAScope in situ hybridization analysis. Chromatin immunoprecipitation assays identified multiple MR response elements (MRE), located from 5 kb upstream of the transcription start site and extending to the third exon of the SLC12A3 gene. Mutation of MRE and SP1 sites in the SLC12A3 promoter region abrogated the transcriptional responses to aldosterone and Vpr, indicating that functional MRE and SP1 are required for the SLC12A3 gene suppression in response to Vpr. Thus, Vpr attenuates MR transcriptional activity and inhibits Slc12a3 transcription in the distal convoluted tubule and contributes to salt wasting in Vpr-transgenic mice.

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Section: Plos Onementioning

confidence: 99%

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

et al. 2022

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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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“…As the two ions co-transported by Ncc, Na + and Cl − have been reported to affect the functional regulation of Ncc. In the tubule epithelial cells of mammalian kidneys, the protein activity and uptake function of Ncc are regulated by intracellular Cl − concentration, which is mediated by post-translational modification via the WNK-SPAK signaling pathways [ 33 , 34 ]. In rodents, the amount of NaCl in the diet affects renal Ncc protein expression and/or its activity [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Physiological Evidence for the Role of Na+-Cl− Co-Transporter in Branchial Na+ Uptake in Freshwater Teleosts

Shih

Yan

Shaochuan

et al. 2023

IJMS

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The gills are the major organ for Na+ uptake in teleosts. It was proposed that freshwater (FW) teleosts adopt Na+/H+ exchanger 3 (Nhe3) as the primary transporter for Na+ uptake and Na+-Cl− co-transporter (Ncc) as the backup transporter. However, convincing molecular physiological evidence to support the role of Ncc in branchial Na+ uptake is still lacking due to the limitations of functional assays in the gills. Thus, this study aimed to reveal the role of branchial Ncc in Na+ uptake with an in vivo detection platform (scanning ion-selective electrode technique, SIET) that has been recently established in fish gills. First, we identified that Ncc2-expressing cells in zebrafish gills are a specific subtype of ionocyte (NCC ionocytes) by using single-cell transcriptome analysis and immunofluorescence. After a long-term low-Na+ FW exposure, zebrafish increased branchial Ncc2 expression and the number of NCC ionocytes and enhanced gill Na+ uptake capacity. Pharmacological treatments further suggested that Na+ is indeed taken up by Ncc, in addition to Nhe, in the gills. These findings reveal the uptake roles of both branchial Ncc and Nhe under FW and shed light on osmoregulatory physiology in adult fish.

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Molecular mechanisms for the modulation of blood pressure and potassium homeostasis by the distal convoluted tubule

Cited by 17 publications

References 130 publications

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

HIV-1 Vpr suppresses expression of the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule

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

Molecular Physiological Evidence for the Role of Na+-Cl− Co-Transporter in Branchial Na+ Uptake in Freshwater Teleosts

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