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Walter F. Boron - One of the best experts on this subject based on the ideXlab platform.
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substrate specificity of the electrogenic sodium bicarbonate cotransporter nbce1 a SLC4A4 variant a from humans and rabbits
American Journal of Physiology-renal Physiology, 2013Co-Authors: Seong-ki Lee, Walter F. Boron, Mark D. ParkerAbstract:In the basolateral membrane of proximal-tubule cells, NBCe1-A (SLC4A4, variant A), operating with an apparent Na+:HCO3− stoichiometry of 1:3, contributes to the reclamation of HCO3− from the glomer...
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Substrate specificity of the electrogenic sodium/bicarbonate cotransporter NBCe1-A (SLC4A4, variant A) from humans and rabbits
American journal of physiology. Renal physiology, 2013Co-Authors: Seong-ki Lee, Walter F. Boron, Mark D. ParkerAbstract:In the basolateral membrane of proximal-tubule cells, NBCe1-A (SLC4A4, variant A), operating with an apparent Na+:HCO3− stoichiometry of 1:3, contributes to the reclamation of HCO3− from the glomer...
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Role of an extracellular loop in determining the stoichiometry of Na+-HCO₃⁻ cotransporters.
The Journal of physiology, 2011Co-Authors: Li-ming Chen, Ying Liu, Walter F. BoronAbstract:The Na+–HCO₃⁻ cotransporters (NBCs) of the solute carrier 4 family (SLC4) are critical for regulating pH in cells as well as in fluids such as blood and cerebrospinal fluid. Moreover, mutations and gene disruptions in NBC are linked to a wide range of pathologies. NBCe1 (SLC4A4) is electrogenic because it has an apparent Na+:HCO₃⁻ stoichiometry of 1:2 or 1:3, whereas NBCn1 (SLC4A7) is electroneutral because it has an apparent stoichiometry of 1:1. Because stoichiometry influences the effect of transport on membrane potential and vice versa, a central question is what structural features underlie electrogenicity versus electroneutrality. A previous study on rat NBCe1/n1 chimeras demonstrated that the structural elements determining the electrogenicity of NBCe1-A are located within the transmembrane domain, excluding the large third extracellular loop. In the present study we generated a series of chimeras of human NBCe1-A and human NBCn1-A. We found that replacing merely the predicted fourth extracellular loop (EL4) – containing 32 amino acid residues that include 7 prolines – of human NBCe1-A with EL4 of NBCn1-A creates an electroneutral NBC. The opposite switch converts an electroneutral construct to one with electrogenic properties. The introduction of an N-glycosylation site into EL4 confirms that at least a part of it is exposed to the extracellular fluid. We hypothesize that putative EL4 either contributes to the substrate-binding vestibule or indirectly influences substrate binding by interacting with one or more transmembrane segments, thereby controlling the nature of transport.
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Cloning, localization, and functional expression of the electrogenic Na+ bicarbonate cotransporter (NBCe1) from zebrafish.
American journal of physiology. Cell physiology, 2009Co-Authors: Caroline R. Sussman, Christopher M. Daly, Jinhua Zhao, Consuelo Plata, Nathan Angle, Jennifer Dipiero, Iain A. Drummond, Jennifer O. Liang, Walter F. BoronAbstract:Mutations in the electrogenic Na+/nHCO3− cotransporter (NBCe1, SLC4A4) cause severe proximal renal tubular acidosis, glaucoma, and cataracts in humans, indicating NBCe1 has a critical role in acid-...
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Use of a new polyclonal antibody to study the distribution and glycosylation of the sodium-coupled bicarbonate transporter NCBE in rodent brain
Neuroscience, 2007Co-Authors: Li-ming Chen, Michelle L. Kelly, Jose D. Rojas, Mark D. Parker, Harindarpal S. Gill, Bruce A. Davis, Walter F. BoronAbstract:Abstract NCBE (SLC4A10) is a member of the SLC4 family of bicarbonate transporters, several of which play important roles in intracellular-pH regulation and transepithelial HCO 3 − transport. Here we characterize a new antibody that was generated in rabbit against a fusion protein consisting of maltose-binding protein and the first 135 amino acids (aa) of the N-terminus of human NCBE. Western blotting—both of purified peptides representing the initial ∼120 aa of the transporters and of full-length transporters expressed in Xenopus oocytes—demonstrated that the antibody is specific for NCBE versus the two most closely related proteins, NDCBE (SLC4A8) and NBCn1 (SLC4A7). Western blotting of tissue in four regions of adult mouse brain indicates that NCBE is expressed most abundantly in cerebral cortex (CX), cerebellum (CB) and hippocampus (HC), and less so in subcortex (SCX). NCBE protein was present in CX, CB, and HC microdissected to avoid choroid plexus. Immunocytochemistry shows that NCBE is present at the basolateral membrane of embryonic day 18 (E18) fetal and adult choroid plexus. NCBE protein is present by Western blot and immunocytochemistry in cultured and freshly dissociated HC neurons but not astrocytes. By Western blot, nearly all NCBE in mouse and rat brain is highly N-glycosylated (∼150 kDa). PNGase F reduces the molecular weight (MW) of natural NCBE in mouse brain or human NCBE expressed in oocytes to approximately the predicted MW of the unglycosylated protein. In oocytes, mutating any one of the three consensus N-glycosylation sites reduces glycosylation of the other two, and the triple mutant exhibits negligible functional expression.
Mark D. Parker - One of the best experts on this subject based on the ideXlab platform.
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Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice.
Journal of the American Society of Nephrology : JASN, 2019Co-Authors: Emily E. Salerno, Sangita P. Patel, Aniko Marshall, Jordan Marshall, Thamer Alsufayan, S. Alassane Mballo, Bianca N. Quade, Mark D. ParkerAbstract:Background The SLC4A4 gene encodes electrogenic sodium bicarbonate cotransporter 1 (NBCe1). Inheritance of recessive mutations in SLC4A4 causes proximal renal tubular acidosis (pRTA), a disease characterized by metabolic acidosis, growth retardation, ocular abnormalities, and often dental abnormalities. Mouse models of pRTA exhibit acidemia, corneal edema, weak dental enamel, impacted colons, nutritional defects, and a general failure to thrive, rarely surviving beyond weaning. Alkali therapy remains the preferred treatment for pRTA, but it is unclear which nonrenal signs are secondary to acidemia and which are a direct consequence of NBCe1 loss from nonrenal sites (such as the eye and enamel organ) and therefore require separate therapy. SLC4A4 encodes three major NBCe1 variants: NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A is expressed in proximal tubule epithelia; its dysfunction causes the plasma bicarbonate insufficiency that underlies acidemia. NBCe1-B and NBCe1-C exhibit a broad extra-proximal-tubular distribution. Methods To explore the consequences of Nbce1b/c loss in the absence of acidemia, we engineered a novel strain of Nbce1b/c-null mice and assessed them for signs of pRTA. Results Nbce1b/c-null mice have normal blood pH, but exhibit increased mortality, growth retardation, corneal edema, and tooth enamel defects. Conclusions The correction of pRTA-related acidemia should not be considered a panacea for all signs of pRTA. The phenotype of Nbce1b/c-null mice highlights the physiologic importance of NBCe1 variants expressed beyond the proximal tubular epithelia and potential limitations of pH correction by alkali therapy in pRTA. It also suggests a novel genetic locus for corneal dystrophy and enamel hypomineralization without acidemia.
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substrate specificity of the electrogenic sodium bicarbonate cotransporter nbce1 a SLC4A4 variant a from humans and rabbits
American Journal of Physiology-renal Physiology, 2013Co-Authors: Seong-ki Lee, Walter F. Boron, Mark D. ParkerAbstract:In the basolateral membrane of proximal-tubule cells, NBCe1-A (SLC4A4, variant A), operating with an apparent Na+:HCO3− stoichiometry of 1:3, contributes to the reclamation of HCO3− from the glomer...
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Substrate specificity of the electrogenic sodium/bicarbonate cotransporter NBCe1-A (SLC4A4, variant A) from humans and rabbits
American journal of physiology. Renal physiology, 2013Co-Authors: Seong-ki Lee, Walter F. Boron, Mark D. ParkerAbstract:In the basolateral membrane of proximal-tubule cells, NBCe1-A (SLC4A4, variant A), operating with an apparent Na+:HCO3− stoichiometry of 1:3, contributes to the reclamation of HCO3− from the glomer...
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Use of a new polyclonal antibody to study the distribution and glycosylation of the sodium-coupled bicarbonate transporter NCBE in rodent brain
Neuroscience, 2007Co-Authors: Li-ming Chen, Michelle L. Kelly, Jose D. Rojas, Mark D. Parker, Harindarpal S. Gill, Bruce A. Davis, Walter F. BoronAbstract:Abstract NCBE (SLC4A10) is a member of the SLC4 family of bicarbonate transporters, several of which play important roles in intracellular-pH regulation and transepithelial HCO 3 − transport. Here we characterize a new antibody that was generated in rabbit against a fusion protein consisting of maltose-binding protein and the first 135 amino acids (aa) of the N-terminus of human NCBE. Western blotting—both of purified peptides representing the initial ∼120 aa of the transporters and of full-length transporters expressed in Xenopus oocytes—demonstrated that the antibody is specific for NCBE versus the two most closely related proteins, NDCBE (SLC4A8) and NBCn1 (SLC4A7). Western blotting of tissue in four regions of adult mouse brain indicates that NCBE is expressed most abundantly in cerebral cortex (CX), cerebellum (CB) and hippocampus (HC), and less so in subcortex (SCX). NCBE protein was present in CX, CB, and HC microdissected to avoid choroid plexus. Immunocytochemistry shows that NCBE is present at the basolateral membrane of embryonic day 18 (E18) fetal and adult choroid plexus. NCBE protein is present by Western blot and immunocytochemistry in cultured and freshly dissociated HC neurons but not astrocytes. By Western blot, nearly all NCBE in mouse and rat brain is highly N-glycosylated (∼150 kDa). PNGase F reduces the molecular weight (MW) of natural NCBE in mouse brain or human NCBE expressed in oocytes to approximately the predicted MW of the unglycosylated protein. In oocytes, mutating any one of the three consensus N-glycosylation sites reduces glycosylation of the other two, and the triple mutant exhibits negligible functional expression.
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The human NBCe1-A mutant R881C, associated with proximal renal tubular acidosis, retains function but is mistargeted in polarized renal epithelia.
American journal of physiology. Cell physiology, 2006Co-Authors: Ashley M. Toye, Mark D. Parker, Christopher M. Daly, Leila V. Virkki, Marc F. Pelletier, Walter F. BoronAbstract:The human electrogenic renal Na-HCO3 cotransporter (NBCe1-A; SLC4A4) is localized to the basolateral membrane of proximal tubule cells. Mutations in the SLC4A4 gene cause an autosomal recessive pro...
Tomohito Mizuno - One of the best experts on this subject based on the ideXlab platform.
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SLC4A4 compound heterozygous mutations in exon intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with turner s syndrome a case report
BMC Medical Genetics, 2018Co-Authors: Shoko Horita, Enver Simsek, Tulay Simsek, Nilgun Yildirim, Hiroyuki Ishiura, Motonobu Nakamura, Nobuhiko Satoh, Atsushi Suzuki, Hiroyuki Tsukada, Tomohito MizunoAbstract:Congenital NBCe1A deficiency with the SLC4A4 mutation causes severe proximal renal tubular acidosis, which often comprises extrarenal symptoms, such as intellectual disability and developmental delay, glaucoma, cataract and band keratopathy. To date, almost all mutations have been found to be homozygous mutations located in exons. We performed direct nucleotide sequencing analysis of exons and exon–intron boundary regions of the SLC4A4 in a patient presenting with severe renal proximal tubule acidosis, glaucoma and intellectual disability and her parents without these signs. The examination revealed compound heterozygous mutations in exon–intron boundary regions, c.1076 + 3A > C and c.1772 − 2A > T, neither of which have been reported previously. While the former mutation was found in the mother, the latter was found in the father. The transcript of the SLC4A4 gene was almost undetectable, and the patient was also diagnosed with Turner’s syndrome. We identified two novel SLC4A4 mutations, c.1076 + 3A > C and c.1772 − 2A > T. When presented in a compound heterozygous state, these mutations caused a phenotype of severe renal proximal tubular acidosis along with glaucoma and mental retardation. This is the first report of congenital proximal renal tubular acidosis carrying compound heterozygous SLC4A4 mutations in exon–intron boundary regions. We suggest that an mRNA surveillance mechanism, nonsense-mediated RNA decay, following aberrant splicing was the reason that the SLC4A4 transcript was almost undetectable in the proband.
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SLC4A4 compound heterozygous mutations in exon–intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner’s syndrome: a case report
BMC medical genetics, 2018Co-Authors: Shoko Horita, Enver Simsek, Tulay Simsek, Nilgun Yildirim, Hiroyuki Ishiura, Motonobu Nakamura, Nobuhiko Satoh, Atsushi Suzuki, Hiroyuki Tsukada, Tomohito MizunoAbstract:Congenital NBCe1A deficiency with the SLC4A4 mutation causes severe proximal renal tubular acidosis, which often comprises extrarenal symptoms, such as intellectual disability and developmental delay, glaucoma, cataract and band keratopathy. To date, almost all mutations have been found to be homozygous mutations located in exons. We performed direct nucleotide sequencing analysis of exons and exon–intron boundary regions of the SLC4A4 in a patient presenting with severe renal proximal tubule acidosis, glaucoma and intellectual disability and her parents without these signs. The examination revealed compound heterozygous mutations in exon–intron boundary regions, c.1076 + 3A > C and c.1772 − 2A > T, neither of which have been reported previously. While the former mutation was found in the mother, the latter was found in the father. The transcript of the SLC4A4 gene was almost undetectable, and the patient was also diagnosed with Turner’s syndrome. We identified two novel SLC4A4 mutations, c.1076 + 3A > C and c.1772 − 2A > T. When presented in a compound heterozygous state, these mutations caused a phenotype of severe renal proximal tubular acidosis along with glaucoma and mental retardation. This is the first report of congenital proximal renal tubular acidosis carrying compound heterozygous SLC4A4 mutations in exon–intron boundary regions. We suggest that an mRNA surveillance mechanism, nonsense-mediated RNA decay, following aberrant splicing was the reason that the SLC4A4 transcript was almost undetectable in the proband.
Michael F. Romero - One of the best experts on this subject based on the ideXlab platform.
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Expression of the Regulated Isoform of the Electrogenic Na+/HCO3- Cotransporter, NBCe1, is Enriched in Pacemaker Interstitial Cells of Cajal.
American journal of physiology. Gastrointestinal and liver physiology, 2020Co-Authors: Maria-gabriela Colmenares Aguilar, Michael F. Romero, Heather L. Holmes, Amelia Mazzone, Seth T. Eisenman, Peter R. Strege, Cheryl E. Bernard, Gianrico Farrugia, Simon J. GibbonsAbstract:Interstitial cells of Cajal (ICC) generate electrical slow waves, which are required for normal gastrointestinal motility. The mechanisms for generation of normal pacemaking are not fully understood. Normal gastrointestinal contractility and electrical slow wave activity depend on the presence of extracellular HCO3-. Previous transcriptional analysis identified enrichment of mRNA encoding the electrogenic Na+/HCO3- cotransporter (NBCe1) gene (SLC4A4) in pacemaker myenteric ICC in mouse small intestine. We aimed to determine the distribution of NBCe1 protein in ICC of the mouse gastrointestinal tract, and to identify the transcripts of the SLC4A4 gene in mouse and human small intestinal tunica muscularis. We determined the distribution of NBCe1-immunoreactivity (NBCe1-IR) by immunofluorescent labeling in mouse and human tissues. In mice, NBCe1-IR was restricted to Kit-positive myenteric ICC of the stomach and small intestine and sub-muscular ICC of the large intestine; that is the slow wave generating subset of ICC. Other sub-types of ICC were NBCe1-negative. Quantitative real time PCR identified >500 fold enrichment of SLC4A4‑207 and SLC4A4‑208 transcripts (IP3-receptor binding protein released by IP3" (IRBIT) regulated isoforms) in Kit expressing cells isolated from KitcreERT2/+, Rpl22tm1.1Psam/Sj mice and from single GFP-positive ICC from Kittm1Rosay mice. Human jejunal tunica muscularis ICC were also NBCe1-positive and SLC4A4‑201 and SLC4A4‑204 RNAs were >300 fold enriched relative to SLC4A4‑202. In summary, NBCe1 protein expressed in ICC with electrical pacemaker function is encoded by SLC4A4 gene transcripts that generate IRBIT regulated isoforms of NBCe1. In conclusion Na+/HCO3- cotransport through NBCe1 contributes to the generation of pacemaker activity in subsets of ICC.
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Expression of the B splice variant of NBCe1 (SLC4A4) in the mouse kidney.
American journal of physiology. Renal physiology, 2018Co-Authors: Lijuan Fang, Michael F. Romero, Hyun-wook Lee, Chao Chen, Autumn N. Harris, Jill W. Verlander, I. David WeinerAbstract:Sodium-coupled bicarbonate transporters are critical for renal electrolyte transport. The electrogenic, sodium-coupled bicarbonate cotransporter, isoform 1 (NBCe1), encoded by the SLC4A4 geneencode...
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Deletion of SLC4A4 in Pancreatic ß Cells Protects from High-Fat Diet–Induced Glucose Intolerance and ß-Cell Dysfunction
Diabetes, 2018Co-Authors: Matthew Brown, Michael F. Romero, Heather L. Holmes, Kuntol Rakshit, Aleksey MatveyenkoAbstract:Islet failure in type 2 diabetes (T2DM) is characterised by loss of glucose-stimulated insulin secretion (GSIS) attributed in part to β-cell dedifferentiation (e.g., mis-expression of alpha cell-specific genes). Recent single cell transcriptomics studies identified SLC4A4 (a gene encoding an electrogenic Na + -nHCO 3 - cotransporter, NBCe1) as one of the mis-expressed genes in β-cells of patients with T2DM. Thus, we set out to test the hypothesis that mis-expression of SLC4A4 in β-cells contributes to loss of GSIS and impaired glucose homeostasis in T2DM. To address this hypothesis, we first confirmed induction of robust SLC4A4 protein expression in β-cells of patients with T2DM utilizing immunofluorescence staining of autopsy-derived human pancreas specimens. We next generated β-cell-specific SLC4A4 knockout (β-SLC4A4 -/- ) and corresponding control (β-SLC4A4 +/+ ) mice through crossing of SLC4A4 loxP/loxP and Ins2-Cre mouse models. Adult (3 month old) β-SLC4A4 -/- mice displayed normal body weight, glycaemia, glucose tolerance and insulin sensitivity under standard chow fed conditions (p>0.vs. β-SLC4A4 +/+ ). In contrast, β-SLC4A4 -/- mice exhibited enhanced glucose tolerance and in vivo glucose-stimulated insulin response under conditions of metabolic stress induced by ad libitum intake of 60% high fat diet (HFD) for 8 weeks (p +/+ HFD). Interestingly, improved glucose tolerance in β-SLC4A4 -/- mice was also associated with a tendency for expansion of β-cells mass (82%, p=0.09 vs. β-SLC4A4 +/+ HFD) and increased β-cells proliferation (26%, p=0.11 vs. β-SLC4A4 +/+ HFD). These results suggest that β-cell mis-expression of the Na + -nHCO 3 - cotransporter encoded by SLC4A4 contributes to induction of β-cell failure under conditions of metabolic stress and T2DM. Disclosure M. Brown: None. H.L. Holmes: None. K. Rakshit: None. M.F. Romero: None. A. Matveyenko: None.
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NBCe1, an Electrogenic Na+ Bicarbonate Cotransporter, in Epithelia
Ion Channels and Transporters of Epithelia in Health and Disease, 2015Co-Authors: Aleksandra Sinđić, Michael F. RomeroAbstract:Na+/bicarbonate (HCO3−) cotransporters (NBCs) are involved in maintaining both cellular and systemic pH homeostasis. Thus far, NBCs are found in the SLC4 gene family, which also includes Na+-independent anion exchangers. Of the ten SLC4 genes, five genes are Na+ bicarbonate cotransport systems: 2 electrogenic transporters, NBCe1 and 2 (SLC4A4 and A5); 2 electroneutral, NBCn1 and 2 (SLC4A7 and A8); and a Na+-driven Cl−/HCO3− exchanger (NDCBE; SLC4A10). There are five NBCe1 isoforms: NBCe1-A (kidney isoform), NBCe1-B (pancreatic and general isoform), NBCe1-C (brain isoform), NBCe1-D, and NBCe1-E (unknown localization). Malfunction of NBCe1 transporters in epithelial cells leads to inappropriate bicarbonate transport and cellular buffering. In humans, recessive NBCe1 (SLC4A4; OMIM #603345) mutations cause development of proximal renal tubular acidosis (pRTA), cataracts, glaucoma, and defective tooth enamel with occasional occurrence of intestinal obstruction. This chapter will focus on physiological and pathological NBCe1 protein function in epithelial tissues, especially those resulting in human disease.
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Metabolic Acidosis, Ocular Pressure and Cysts in NBCe1 Knockout
The FASEB Journal, 2015Co-Authors: Jordan Hildenbrand, Heather L. Holmes, An-ping Chen, Greg M. Landry, Min-hwang Chang, Michael F. RomeroAbstract:Background: Human mutations in the Na+ bicarbonate cotransporter NBCe1 (SLC4A4) cause proximal renal tubular acidosis (pRTA), cataracts & glaucoma. We reported that whole-gene nbce1 knockouts (KO) ...
Naguib Salleh - One of the best experts on this subject based on the ideXlab platform.
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Isoflavone genistein inhibits estrogen‐induced chloride and bicarbonate secretory mechanisms in the uterus in rats
Journal of biochemical and molecular toxicology, 2016Co-Authors: Asma Chinigarzadeh, Kamarulzaman Karim, Sekaran Muniandy, Naguib SallehAbstract:We hypothesized that genistein could affect the chloride (Cl−) and bicarbonate (HCO3−) secretory mechanisms in uterus. Ovariectomized female rats were given estradiol or estradiol plus progesterone with 25, 50, or 100 mg/kg/day genistein. Following completion of the treatment, uterine fluid Cl− and HCO3− concentrations were determined by in vivo uterine perfusion. Uteri were subjected for molecular biological analysis (Western blot, qPCR, and immunohistochemistry) to detect levels of expression of Cystic Fibrosis transmembrane regulator (CFTR), Cl−/HCO3− exchanger (SLC26a6), Na+/HCO3− cotransporter (SLC4A4), and estrogen receptor (ER)-α and β. Coadministration of genistein resulted in decrease in Cl− and HCO3− concentrations and expression of CFTR, SLC26a6, SLC4A4, and ER-α and ER-β in the uteri of estradiol-treated rats. In estradiol plus progesterone-treated rats, a significant increase in the above parameters were observed following high-dose genistein treatment except for the SLC24a4 level. In conclusion, genistein-induced changes in the uterus could affect the reproductive processes that might result in infertility.
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modulation of sodium bicarbonate co transporter SLC4A4 nbce1 protein and mrna expression in rat s uteri by sex steroids and at different phases of the oestrous cycle
Research in Veterinary Science, 2014Co-Authors: Khadijeh Gholami, Sekaran Muniandy, Naguib SallehAbstract:Abstract Oestrogen-induced uterine fluid sodium (Na+) and bicarbonate ( HCO 3 - ) secretion may involve SLC4A4. We hypothesized that uterine SLC4A4 expression changes under different sex-steroid influence, therefore may account for the fluctuation in uterine fluid Na+ and HCO 3 - content throughout the oestrous cycle. The aim of this study is to investigate the differential effects of sex-steroids and oestrous cycle phases on uterine SLC4A4 expression. Methods: Adult female WKY rats were ovariectomised and treated with different doses of 17β-oestradiol (E2) (0.2, 2, 20 and 50 μg/ml/day) or progesterone (P4) (4 mg/ml/day) for three consecutive days and 3 days treatment with 0.2 μg/ml/day E2 followed by another 3 days with P4 to mimic the hormonal changes in early pregnancy. Oestrous cycle phases in intact, non-ovariectomised rats were determined by vaginal smear. The animals were then sacrificed and uteri were removed for protein and mRNA expression analyses by Western blotting and Real Time PCR, respectively. SLC4A4 distribution was observed by immunohistochemistry. Results: Treatment with increasing E2 doses resulted in a dose-dependent increase in SLC4A4 protein expression. High SLC4A4 protein and mRNA expression can be seen at estrus. SLC4A4 is distributed mainly at the apical as well as basolateral membranes of the luminal and glandular epithelia following E2 treatment and at Es. Meanwhile, SLC4A4 expression was reduced following P4 treatment and was low at diestrus. Conclusion: High SLC4A4 expression under estrogen dominance may contribute to the increase in uterine fluid Na+ and HCO 3 - content, while its low expression under P4 dominance may result in vice versa.
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Modulation of sodium-bicarbonate co-transporter (SLC4A4/NBCe1) protein and mRNA expression in rat's uteri by sex-steroids and at different phases of the oestrous cycle.
Research in veterinary science, 2013Co-Authors: Khadijeh Gholami, Sekaran Muniandy, Naguib SallehAbstract:Abstract Oestrogen-induced uterine fluid sodium (Na+) and bicarbonate ( HCO 3 - ) secretion may involve SLC4A4. We hypothesized that uterine SLC4A4 expression changes under different sex-steroid influence, therefore may account for the fluctuation in uterine fluid Na+ and HCO 3 - content throughout the oestrous cycle. The aim of this study is to investigate the differential effects of sex-steroids and oestrous cycle phases on uterine SLC4A4 expression. Methods: Adult female WKY rats were ovariectomised and treated with different doses of 17β-oestradiol (E2) (0.2, 2, 20 and 50 μg/ml/day) or progesterone (P4) (4 mg/ml/day) for three consecutive days and 3 days treatment with 0.2 μg/ml/day E2 followed by another 3 days with P4 to mimic the hormonal changes in early pregnancy. Oestrous cycle phases in intact, non-ovariectomised rats were determined by vaginal smear. The animals were then sacrificed and uteri were removed for protein and mRNA expression analyses by Western blotting and Real Time PCR, respectively. SLC4A4 distribution was observed by immunohistochemistry. Results: Treatment with increasing E2 doses resulted in a dose-dependent increase in SLC4A4 protein expression. High SLC4A4 protein and mRNA expression can be seen at estrus. SLC4A4 is distributed mainly at the apical as well as basolateral membranes of the luminal and glandular epithelia following E2 treatment and at Es. Meanwhile, SLC4A4 expression was reduced following P4 treatment and was low at diestrus. Conclusion: High SLC4A4 expression under estrogen dominance may contribute to the increase in uterine fluid Na+ and HCO 3 - content, while its low expression under P4 dominance may result in vice versa.