Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney

Obermüller, Nicholas; Bernstein, Paul; Velázquez, Heino; Reilly, Robert F.; Moser, Doris; Ellison, David H.; Bachmann, S.

doi:10.1152/ajprenal.1995.269.6.f900

Cited by 146 publications

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“…From each rat 6 -10 cells were analyzed on sections oriented approximately at right angle to the apical cell membrane. The cells originated both from DCT1 and DCT2 (7,27). Gold particles were ascribed to the apical cell membrane when located on its outer surface, directly above, or within 30 nm from its inner surface.…”

Section: Methodsmentioning

confidence: 99%

ANG II provokes acute trafficking of distal tubule Na⁺-Cl⁻cotransporter to apical membrane

Sandberg¹,

Riquier²,

Pihakaski-Maunsbach³

et al. 2007

American Journal of Physiology-Renal Physiology

139

149

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May 16, 2007; doi:10.1152/ajprenal.00064.2007.-The distal convoluted tubule (DCT) Na ϩ -Cl Ϫ cotransporter (NCC), the target of thiazide diuretics, is responsible for the reabsorption of 5-10% of filtered NaCl. The aim of this study was to test the hypothesis that acute infusion of the angiotensin-converting enzyme (ACE) inhibitor captopril (at 12 g/min) for 20 min provokes trafficking of NCC from apical plasma membranes (APM) to subapical cytoplasmic vesicles (SCV), which is reversed by acute ANG II infusion (ANG II at 20 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 along with 12 g/min captopril) for 20 min in male Sprague-Dawley rats (250 -350 g). By immuno-electron microscopy using an anti-NCC (D. Ellison) 71.5 Ϯ SD 4.9% of the NCC gold labeling was associated with the APM in control, sham operated, and infused rats, while captopril infusion reduced NCC in APM to 54.9 Ϯ 6.9% (P Ͻ 0.001) and markedly increased immunogold labeling of SCV. Subsequent infusion of ANG II with captopril restored NCC immunogold labeling of APM to 72.4 Ϯ 4.2%, that is, 20% of the total NCC trafficked between APM and SCV. Likewise, on density gradients of cortex, captopril provoked redistribution of 27.3% of total NCC from low-density APM-enriched membranes to higher-density membranes and ANG IIϩcaptopril restored 20.3% of the NCC to APM-enriched fractions. Redistribution occurred independent of a change in NCC total abundance. In conclusion, this study demonstrates that ACE inhibition provokes acute trafficking of NCC out of the plasma membrane, which likely decreases DCT Na ϩ reabsorption, while ANG II provokes rapid trafficking of NCC from stores in subapical vesicles to the plasma membrane, which likely increases DCT Na ϩ reabsorption. sodium transport; thiazide receptor; immunoelectron microscopy THE NA ϩ -CL Ϫ COTRANSPORTER (NCC) is expressed in the apical membrane of the distal convoluted tubule (DCT) and is the target of the thiazide diuretics, which are frequently used in the treatment of hypertension and edema (1, 29). The importance of NCC in the regulation of blood pressure and salt balance is demonstrated in the genetic disorder Gitelman's syndrome in which loss of function mutations in NCC results in salt wasting, hypokalemia, and hypotension (32). Studies in mice with NCC knocked out show that on low-sodium diets, blood pressure is significantly reduced from control (31).There are multiple mechanisms by which NCC could be regulated to control Na ϩ transport in the DCT. Many studies have shown that NCC abundance is regulated by stimuli, such as dietary salt, aldosterone escape, and mineralocorticoid receptor blockade (22,26,33,36), less is known about trafficking of NCC to and from the apical membrane as a way of regulating NCC. The potential importance of trafficking in the regulation of NCC has been demonstrated in vitro in Gitelman's syndrome where oocyte studies indicate that NCC is not processed properly in the endoplasmic reticulum, resulting in deficient trafficking of NCC to the plasma membrane (8,14). A previous study from this labora...

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Section: Methodsmentioning

confidence: 99%

ANG II provokes acute trafficking of distal tubule Na⁺-Cl⁻cotransporter to apical membrane

Sandberg¹,

Riquier²,

Pihakaski-Maunsbach³

et al. 2007

American Journal of Physiology-Renal Physiology

139

149

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“…The disease is due to loss of function mutations in the SLC12A3 gene (16q13) that codes for the thiazide-sensitive NaCl co-transporter (NCC) (2)(3)(4)(5)(6)(7)(8)(9)(10). NCC is a 1021-amino acid integral membrane protein that is expressed mainly in the epithelial cells of the renal distal convoluted tubule (DCT), where it is responsible for the reabsorption of 5 to 10% of filtered Na ϩ and Cl Ϫ (11). Loss-of-function mutations of NCC explain the clinical manifestations of GS, which are similar to the prolonged administration of thiazide diuretics (12).…”

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confidence: 99%

Transcriptional and Functional Analyses of SLC12A3 Mutations

Riveira-Muñoz¹,

Chang²,

Godefroid³

et al. 2007

Journal of the American Society of Nephrology

142

123

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Gitelman syndrome (GS) is a recessive salt-losing tubulopathy that is caused by mutations in the SLC12A3 gene that encodes the sodium-chloride co-transporter (NCC). GS is characterized by significant inter-and intrafamilial phenotype variability, with early onset and/or severe clinical manifestations in some patients. No correlations between the disease variability and the position/nature of SLC12A3 mutations have been investigated thus far. In this study, extensive mutational analyses of SLC12A3 were performed in 27 patients with GS, including genomic DNA sequencing, multiplex ligation-dependent probe amplification, cDNA analysis, and quantification of allele-specific transcripts, in parallel with functional analyses in Xenopus laevis oocytes and detailed phenotyping. Twenty-six SLC12A3 mutations were identified in 25 patients with GS, including eight novel (detection rate 80%). Transcript analysis demonstrated that splicing mutations of SLC12A3 lead to frameshifted mRNA subject to degradation by nonsense-mediated decay. Heterologous expression documented a novel class of NCC mutants with defective intrinsic transport activity. A subgroup of patients presented with early onset, growth retardation, and/or detrimental manifestations, confirming the potential severity of GS. The mutations that were associated with a severe presentation were the combination at least for one allele of a missplicing resulting in a truncated transcript that was downregulated by nonsense-mediated decay or a nonfunctional, cell surface-absent mutant. The most recurrent mutation on the second allele was a newly described NCC mutant that affected the functional properties of the co-transporter. These data suggest that the nature/position of SLC12A3 mutation, combined with male gender, is a determinant factor in the severity of GS and provide new insights in the underlying pathogenic mechanisms of the disease.

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“…Thiazide diuretics used in patients who are at an increased risk for developing hyperkalemia [1]. Thiazides achieve their diuretic action via inhibition of the Na + /Cl − cotransporter (NCC) in the renal distal convoluted tubule [2][3][4]. The NCC facilitates the absorption of sodium from the distal tubules back to the interstitium and accounts for approximately 7% of total sodium reabsorption [5].…”

Section: Introductionmentioning

confidence: 99%

Analytical Techniques for Determination of Hydrochlorothiazide and its Combinations: A Review

Savaj¹,

Patidar²,

Raj³

2015

Int J of Adv in Sci Res

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Hydrochlorothiazide is chemically 6-chloro-1, 1-dioxo-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide. Hydrochlorothiazide is a diuretic drug used for treatment of high blood pressure (hypertension) and accumulation of fluid (edema). It works by blocking salt and fluid reabsorption from the urine in the kidneys, causing increased urine output (dieresis). Hydrochlorothiazide is used to treat excessive fluid accumulation and swelling (edema) of the body caused by heart failure, cirrhosis, chronic kidney failure, corticosteroid medications, and nephrotic syndrome. It can be used alone or in conjunction with other blood pressure lowering medications to treat high blood pressure.This review focuses on the recent developments in analytical techniques for estimation of Hydrochlorothiazide alone or in combinations with other drugs in various biological media like human plasma and urine. This review will critically examine the (a) sample pretreatment method such as solid phase extraction (SPE), (b) separation methods such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC), high performance thin layer chromatography (HPTLC), liquid chromatography coupled to tandem mass spectrometry (LC-MS) and capillary electrophoresis (CE), (c) other methods such as spectrophotometry, diffuse reflectance near infrared spectroscopy and electrochemical methods.

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Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney

Cited by 146 publications

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ANG II provokes acute trafficking of distal tubule Na⁺-Cl⁻cotransporter to apical membrane

ANG II provokes acute trafficking of distal tubule Na⁺-Cl⁻cotransporter to apical membrane

Transcriptional and Functional Analyses of SLC12A3 Mutations

Analytical Techniques for Determination of Hydrochlorothiazide and its Combinations: A Review

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Expression of the thiazide-sensitive Na-Cl cotransporter in rat and human kidney

Cited by 146 publications

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ANG II provokes acute trafficking of distal tubule Na+-Cl−cotransporter to apical membrane

ANG II provokes acute trafficking of distal tubule Na+-Cl−cotransporter to apical membrane

Transcriptional and Functional Analyses of SLC12A3 Mutations

Analytical Techniques for Determination of Hydrochlorothiazide and its Combinations: A Review

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ANG II provokes acute trafficking of distal tubule Na⁺-Cl⁻cotransporter to apical membrane

ANG II provokes acute trafficking of distal tubule Na⁺-Cl⁻cotransporter to apical membrane