Rabbit distal convoluted tubule coexpresses NaCl cotransporter and 11β-hydroxysteroid dehydrogenase II mRNA

Velázquez, Heino; Náray-Fejes-Tóth, Anikó; Silva, Teresa; Andújar, Eleanor; Reilly, Robert F.; Desir, Gary V.; Ellison, David H.

doi:10.1046/j.1523-1755.1998.00036.x

Cited by 50 publications

(42 citation statements)

References 27 publications

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“…The unambiguous identification of DCT cells is critical; it is necessary to show coexpression of 11bHSD2 with NCC. This has been shown in the rabbit, 40 so the ASDN comprises DCT, CNT, and CCD in this species. The presumption that the DCT .…”

Section: Molecular Definition Of the Asdnsupporting

confidence: 58%

Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model

Hunter

Ivy

Flatman

et al. 2015

Journal of the American Society of Nephrology

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Na+ transport in the renal distal convoluted tubule (DCT) by the thiazide-sensitive NaCl cotransporter (NCC) is a major determinant of total body Na + and BP. NCC-mediated transport is stimulated by aldosterone, the dominant regulator of chronic Na + homeostasis, but the mechanism is controversial. Transport may also be affected by epithelial remodeling, which occurs in the DCT in response to chronic perturbations in electrolyte homeostasis. Hsd11b2 2/2 mice, which lack the enzyme 11b-hydroxysteroid dehydrogenase type 2 (11bHSD2) and thus exhibit the syndrome of apparent mineralocorticoid excess, provided an ideal model in which to investigate the potential for DCT hypertrophy to contribute to Na + retention in a hypertensive condition. The DCTs of Hsd11b2 2/2 mice exhibited hypertrophy and hyperplasia and the kidneys expressed higher levels of total and phosphorylated NCC compared with those of wild-type mice. However, the striking structural and molecular phenotypes were not associated with an increase in the natriuretic effect of thiazide. In wild-type mice, Hsd11b2 mRNA was detected in some tubule segments expressing Slc12a3, but 11bHSD2 and NCC did not colocalize at the protein level. Thus, the phosphorylation status of NCC may not necessarily equate to its activity in vivo, and the structural remodeling of the DCT in the knockout mouse may not be a direct consequence of aberrant corticosteroid signaling in DCT cells. These observations suggest that the conventional concept of mineralocorticoid signaling in the DCT should be revised to recognize the complexity of NCC regulation by corticosteroids.

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Section: Molecular Definition Of the Asdnsupporting

confidence: 58%

Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model

Hunter

Ivy

Flatman

et al. 2015

Journal of the American Society of Nephrology

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“…This increase in affinity for Cl Ϫ was specific for this ion because no change was observed in the affinity for extracellular Na ϩ . Glycine is a non-hydrophobic residue at position 264, which is predicted to be located in the TSC putative transmembrane domain 4 and is conserved in all species in which TSC has been sequenced, including human (8), rat (25), mouse (27), rabbit (26), and flounder (2), as well as among all members of the SLC12 family including TSC, two Na ϩ :K ϩ :2Cl Ϫ , and four K ϩ :Cl Ϫ cotransporter isoforms. Previous studies in the basolateral isoform of the Na ϩ :K ϩ :2Cl Ϫ cotransporter (18,45) indicated that transmembrane helix 4 contains affinity-modifying residues for Cl Ϫ translocation.…”

Section: Discussionmentioning

confidence: 99%

“…Two SNPs result in a single amino acid change. One is the R863K SNP (cluster ID rs8060046) that was considered as irrelevant because this SNP located within the carboxyl-terminal domain results in a conserved substitution of the positively charged amino acid arginine, which is present in the human cotransporter (8), for the positively charged residue lysine, which is present in the TSC from rabbit, rat, mouse, and fish (2,(25)(26)(27). In contrast, the other SNP that alter the primary sequence of human TSC (ID number rs1529927) predicts a change of the nonpolar amino acid glycine at the position 264 for the residue alanine.…”

Section: Single Nucleotide Polymorphisms In the Slc12a3mentioning

confidence: 99%

“…In contrast, the other SNP that alter the primary sequence of human TSC (ID number rs1529927) predicts a change of the nonpolar amino acid glycine at the position 264 for the residue alanine. The residue glycine is located within the fourth transmembrane domain and is a conserved amino acid residue, not only in the available TSC sequences from rat (25), mouse (27), rabbit (26), human (8), and flounder (2), but also in all members of SLC12 family that include two genes encoding Na ϩ :K ϩ :2Cl Ϫ cotransporters (25,28) and four genes encoding K ϩ :Cl Ϫ cotransporters (29 -31). Thus, the G264A SNP was considered as potentially important and therefore was introduced into TSC by in vitro mutagenesis.…”

Section: Single Nucleotide Polymorphisms In the Slc12a3mentioning

confidence: 99%

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A Single Nucleotide Polymorphism Alters the Activity of the Renal Na+:Cl- Cotransporter and Reveals a Role for Transmembrane Segment 4 in Chloride and Thiazide Affinity

Moreno

Tovar‐Palacio

Heros

et al. 2004

Journal of Biological Chemistry

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The thiazide-sensitive Na ؉ :Cl ؊ cotransporter is the major salt transport pathway in the distal convoluted tubule of the kidney, and a role of this cotransporter in blood pressure homeostasis has been defined by physiological studies on pressure natriuresis and by its involvement in monogenic diseases that feature arterial hypotension or hypertension. Data base analysis revealed that 135 single nucleotide polymorphisms along the human SLC12A3 gene that encodes the Na ؉ :Cl ؊ cotransporter have been reported. Eight are located within the coding region, and one results in a single amino acid change; the residue glycine at the position 264 is changed to alanine (G264A). This residue is located within the fourth transmembrane domain of the predicted structure. Because Gly-264 is a highly conserved residue, we studied the functional properties of this polymorphism by using in vitro mutagenesis and the heterologous expression system in Xenopus laevis oocytes. G264A resulted in a significant and reproducible reduction (ϳ50%) in 22 Na ؉ uptake when compared with the wild type cotransporter. The affinity for extracellular Cl ؊ and for thiazide diuretics was increased in G264A. Western blot analysis showed similar immunoreactive bands between the wild type and the G264A cotransporters, and confocal images of oocytes injected with enhanced green fluorescent protein-tagged wild type and G264A cotransporter showed no differences in the protein surface expression level. These observations suggest that the G264A polymorphism is associated with reduction in the substrate translocation rate of the cotransporter, due to a decrease in the intrinsic activity. Our study also reveals a role of the transmembrane segment 4 in defining the affinity for extracellular Cl ؊ and thiazide diuretics.

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“…There is evidence suggesting that salt transport by this nephron segment may also be regulated by aldosterone. Components of the mineralocorticoid receptor system, including the MR and the 11␤HSD2, have been found to be expressed by distal convoluted tubule cells along with the Na-Cl cotransporter, indicating that these cells are also targets of aldosterone action, possibly improving sodium recovery in low salt and volume states (17,36). In experimental animals, sites with the highest manifestation of the calcium-extruding machinery, including the recently discovered renal epithelial calcium channel, ECaC1 or CaT2 (37,38) were identified in the connecting tubule and distal convoluted tubule and colocalized with the epithelial sodium channel (39).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Renal Calcium Handling by 11β-Hydroxysteroid Dehydrogenase Type 2

Ferrari

Bianchetti²,

Sansonnens³

et al. 2002

Journal of the American Society of Nephrology

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Abstract. Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11␤-hydroxysteroid dehydrogenase type 2 (11␤HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11␤HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THFϩ5␣THF)/THE as a parameter of 11␤HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THFϩ5␣THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 Ϯ 10/7 versus 115/73 Ϯ 8/6 mmHg; P Ͻ 0.001 for systolic; P Ͻ 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 Ϯ 0.05 to 1.18 Ϯ 0.04 mmol/L (P Ͻ 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 Ϯ 3.6 to 31.9 Ϯ 3.1 mol/L GFR (P Ͻ 0.01). Fractional calcium excretion increased from 2.4 Ϯ 0.3 to 2.7 Ϯ 0.3% (P Ͻ 0.01) and was negatively correlated to the fractional sodium excretion during GA (R ϭ Ϫ0.35; P Ͻ 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R ϭ 0.66; P Ͻ 0.0001). Inhibition of 11␤HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this divalent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule.

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Rabbit distal convoluted tubule coexpresses NaCl cotransporter and 11β-hydroxysteroid dehydrogenase II mRNA

Abstract: We conclude that the DCT is a target tissue for the action of aldosterone. Axial heterogeneity of electroneutral (in DCT) and electrogenic (in CCD) Na transporters along the distal nephron may improve sodium recovery in low salt and volume states.

Cited by 50 publications

References 27 publications

Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model

Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model

A Single Nucleotide Polymorphism Alters the Activity of the Renal Na+:Cl- Cotransporter and Reveals a Role for Transmembrane Segment 4 in Chloride and Thiazide Affinity

Modulation of Renal Calcium Handling by 11β-Hydroxysteroid Dehydrogenase Type 2

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