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Snoozy J, Bhattacharya S, Fettig RR, Van Asma A, Brede C, Warnhoff K. XDH-1 inactivation causes xanthine stone formation in C. elegans which is inhibited by SULP-4-mediated anion exchange in the excretory cell. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.24.634556. [PMID: 39975063 PMCID: PMC11838210 DOI: 10.1101/2025.01.24.634556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Xanthine dehydrogenase (XDH-1) is a molybdenum cofactor (Moco) requiring enzyme that catabolizes hypoxanthine into xanthine and xanthine into uric acid, the final steps in purine catabolism. Human patients with mutations in xdh-1 develop xanthinuria which can lead to xanthine stones in the kidney, recurrent urinary tract infections, and renal failure. Currently there are no therapies for treating human XDH-1 deficiency. Thus, understanding mechanisms that maintain purine homeostasis is an important goal of human health. Here, we used the nematode C. elegans to model human XDH-1 deficiency using 2 clinically relevant paradigms, Moco deficiency or loss-of-function mutations in xdh-1. Both Moco deficiency and xdh-1 mutations caused the formation of autofluorescent xanthine stones in C. elegans. Surprisingly, only 2% of xdh-1 null mutant C. elegans developed a xanthine stone, suggesting additional pathways may regulate this process. To uncover such pathways, we performed a forward genetic screen for mutations that enhance the penetrance of xanthine stone formation in xdh-1 null mutant C. elegans. We isolated multiple loss-of-function mutations in the gene sulp-4 which encodes a transmembrane transport protein homologous to human SLC26 anion exchange proteins. We demonstrated that SULP-4 acts cell-nonautonomously in the excretory cell to limit xanthine stone accumulation. Interestingly, sulp-4 mutant phenotypes were suppressed by mutations in genes that encode for cystathionase (cth-2) or cysteine dioxygenase (cdo-1), members of the sulfur amino acid metabolism pathway required for production of the osmolyte taurine. Furthermore, cdo-1 mRNA accumulated in sulp-4 mutant animals, mirroring cdo-1 activation observed during hyperosmotic stress in C. elegans and mammals. We propose that loss of SULP-4-mediated anion exchange causes osmotic stress and cdo-1 activation, a maladaptive response that promotes xanthine stone accumulation. Supporting the model that the osmotic stress response impacts xanthine stone accumulation, a mutation in osm-8 that constitutively activates the osmotic stress response, also promoted xanthine stone accumulation in an xdh-1 mutant background. Thus, our work establishes a C. elegans model for human XDH-1 deficiency and identifies sulp-4 and the osmotic stress response governed by cdo-1 as critical players in controlling xanthine stone accumulation.
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Affiliation(s)
- Jennifer Snoozy
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Sushila Bhattacharya
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Robin R. Fettig
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
- Department of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA
| | | | - Chloe Brede
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
| | - Kurt Warnhoff
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105 USA
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Mariscal de Gante L, Salanova L, Valdivia Mazeyra M, Serrano Pardo R, Quiroga B. Secondary hyperoxaluria: Cause and consequence of chronic kidney disease. Nefrologia 2025; 45:5-14. [PMID: 39800598 DOI: 10.1016/j.nefroe.2024.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 06/08/2024] [Indexed: 02/01/2025] Open
Abstract
Secondary hyperoxaluria is a metabolic disorder characterized by an increase in urinary oxalate excretion. The etiology may arise from an increase in the intake of oxalate or its precursors, decreased elimination at the digestive level, or heightened renal excretion. Recently, the role of the SLC26A6 transporter in the etiopathogenesis of this disease has been identified. This transporter is active at both the intestinal and renal levels, and its mechanism of action is disrupted during systemic inflammation and metabolic syndrome, which could explain the rising incidence of secondary hyperoxaluria in recent decades. Treatment includes hygienic dietary measures, and medications aimed at reducing intestinal absorption by increasing fecal excretion. Different immunomodulatory drugs, microbiome modifiers and SGLT2 inhibitors could constitute new therapeutic targets. Currently, specific treatments for secondary hyperoxaluria are lacking, making early diagnosis and preventive measures against kidney failure the main therapeutic strategies.
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Affiliation(s)
| | - Laura Salanova
- Servicio de Nefrología, Hospital Universitario de la Princesa, Madrid, Spain
| | | | - Rosario Serrano Pardo
- Servicio de Anatomía Patológica, Hospital Universitario de la Princesa, Madrid, Spain
| | - Borja Quiroga
- Servicio de Nefrología, Hospital Universitario de la Princesa, Madrid, Spain.
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Yang W, Zhao T, Chen X, Wang S, Wang Y, Su T. Determinants and impact of calcium oxalate crystal deposition on renal outcomes in acute kidney injury patients. Ren Fail 2024; 46:2334396. [PMID: 38570195 PMCID: PMC10993744 DOI: 10.1080/0886022x.2024.2334396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 03/19/2024] [Indexed: 04/05/2024] Open
Abstract
OBJECTIVES Calcium oxalate (CaOx) crystal deposition in acute kidney injury (AKI) patients is under recognized but impacts renal outcomes. This study investigates its determinants and effects. METHODS We studied 814 AKI patients with native kidney biopsies from 2011 to 2020, identifying CaOx crystal deposition severity (mild: <5, moderate: 5-10, severe: >10 crystals per section). We assessed factors like urinary oxalate, citrate, urate, electrolytes, pH, tubular calcification index, and SLC26A6 expression, comparing them with creatinine-matched AKI controls without oxalosis. We analyzed how these factors relate to CaOx severity and their impact on renal recovery (eGFR < 15 mL/min/1.73 m2 at 3-month follow-up). RESULTS CaOx crystal deposition was found in 3.9% of the AKI cohort (32 cases), with 72% due to nephrotoxic medication-induced tubulointerstitial nephritis. Diuretic use, higher urinary oxalate-to-citrate ratio induced by hypocitraturia, and tubular calcification index were significant contributors to moderate and/or severe CaOx deposition. Poor baseline renal function, low urinary chloride, high uric acid and urea nitrogen, tubular SLC26A6 overexpression, and glomerular sclerosis were also associated with moderate-to-severe CaOx deposition. Kidney recovery was delayed, with 43.8%, 31.2%, and 18.8% of patients having eGFR < 15 mL/min/1.73 m2 at 4, 12, and 24-week post-injury. Poor outcomes were linked to high urinary α1-microglobulin-to-creatinine (α1-MG/C) ratios and active tubular injury scores. Univariate analysis showed a strong link between this ratio and poor renal outcomes, independent of oxalosis severity. CONCLUSIONS In AKI, CaOx deposition is common despite declining GFR. Factors worsening tubular injury, not just oxalate-to-citrate ratios, are key to understanding impaired renal recovery.
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Affiliation(s)
- Weiwei Yang
- Department of medicine, Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, PR China
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, PR China
| | - Tao Zhao
- Department of medicine, Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, PR China
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, PR China
| | - Xuejing Chen
- Department of medicine, Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, PR China
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, PR China
| | - Suxia Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, PR China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, PR China
| | - Yu Wang
- Department of medicine, Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, PR China
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, PR China
| | - Tao Su
- Department of medicine, Renal Division, Peking University First Hospital, Peking University, Institute of Nephrology, Renal Pathology Center, Institute of Nephrology, Peking University, Beijing, PR China
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, PR China
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Xu J, Barone S, Varasteh Kia M, Holliday LS, Zahedi K, Soleimani M. Identification of IQGAP1 as a SLC26A4 (Pendrin)-Binding Protein in the Kidney. Front Mol Biosci 2022; 9:874186. [PMID: 35601831 PMCID: PMC9117723 DOI: 10.3389/fmolb.2022.874186] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 03/22/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Several members of the SLC26A family of transporters, including SLC26A3 (DRA), SLC26A5 (prestin), SLC26A6 (PAT-1; CFEX) and SLC26A9, form multi-protein complexes with a number of molecules (e.g., cytoskeletal proteins, anchoring or adaptor proteins, cystic fibrosis transmembrane conductance regulator, and protein kinases). These interactions provide regulatory signals for these molecules. However, the identity of proteins that interact with the Cl-/HCO3 - exchanger, SLC26A4 (pendrin), have yet to be determined. The purpose of this study is to identify the protein(s) that interact with pendrin. Methods: A yeast two hybrid (Y2H) system was employed to screen a mouse kidney cDNA library using the C-terminal fragment of SLC26A4 as bait. Immunofluorescence microscopic examination of kidney sections, as well as co-immunoprecipitation assays, were performed using affinity purified antibodies and kidney protein extracts to confirm the co-localization and interaction of pendrin and the identified binding partners. Co-expression studies were carried out in cultured cells to examine the effect of binding partners on pendrin trafficking and activity. Results: The Y2H studies identified IQ motif-containing GTPase-activating protein 1 (IQGAP1) as a protein that binds to SLC26A4's C-terminus. Co-immunoprecipitation experiments using affinity purified anti-IQGAP1 antibodies followed by western blot analysis of kidney protein eluates using pendrin-specific antibodies confirmed the interaction of pendrin and IQGAP1. Immunofluorescence microscopy studies demonstrated that IQGAP1 co-localizes with pendrin on the apical membrane of B-intercalated cells, whereas it shows basolateral expression in A-intercalated cells in the cortical collecting duct (CCD). Functional and confocal studies in HEK-293 cells, as well as confocal studies in MDCK cells, demonstrated that the co-transfection of pendrin and IQGAP1 shows strong co-localization of the two molecules on the plasma membrane along with enhanced Cl-/HCO3 - exchanger activity. Conclusion: IQGAP1 was identified as a protein that binds to the C-terminus of pendrin in B-intercalated cells. IQGAP1 co-localized with pendrin on the apical membrane of B-intercalated cells. Co-expression of IQGAP1 with pendrin resulted in strong co-localization of the two molecules and increased the activity of pendrin in the plasma membrane in cultured cells. We propose that pendrin's interaction with IQGAP1 may play a critical role in the regulation of CCD function and physiology, and that disruption of this interaction could contribute to altered pendrin trafficking and/or activity in pathophysiologic states.
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Affiliation(s)
- Jie Xu
- Research Services, VA Medical Center, Albuquerque, NM, United States,Department of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Sharon Barone
- Research Services, VA Medical Center, Albuquerque, NM, United States,Department of Medicine, University of Cincinnati, Cincinnati, OH, United States,Department of Medicine, University of New Mexico, Albuquerque, NM, United States
| | - Mujan Varasteh Kia
- Department of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - L. Shannon Holliday
- Department of Orthodontics, University of Florida, Gainesville, FL, United States
| | - Kamyar Zahedi
- Research Services, VA Medical Center, Albuquerque, NM, United States,Department of Medicine, University of Cincinnati, Cincinnati, OH, United States,Department of Medicine, University of New Mexico, Albuquerque, NM, United States
| | - Manoocher Soleimani
- Research Services, VA Medical Center, Albuquerque, NM, United States,Department of Medicine, University of Cincinnati, Cincinnati, OH, United States,Department of Medicine, University of New Mexico, Albuquerque, NM, United States,*Correspondence: Manoocher Soleimani,
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5
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Zhang R, Ji J, Li Y, Yu J, Yu X, Xu Y. Molecular Characterization and RNA Interference Analysis of SLC26A10 From Nilaparvata lugens (Stål). Front Physiol 2022; 13:853956. [PMID: 35370768 PMCID: PMC8969416 DOI: 10.3389/fphys.2022.853956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/17/2022] [Indexed: 11/13/2022] Open
Abstract
SLC26A10 is a member of the SLC26 gene family, but its role in insects is still unclear. We cloned the SLC26A10 gene of Nilaparvata lugens (NlSLC26A10) and found NlSLC26A10 contained 11 transmembrane regions and a STAS domain. Expression pattern analysis showed NlSLC26A10 expression was more upregulated in adults than in nymphs, highest in the ovary. After injection of double-stranded RNA (dsRNA) of NlSLC26A10, the mRNA level of NlSLC26A10 significantly decreased and, consequently, the ovarian development of adult females was hindered; the amount and the hatchability of eggs and yeast-like symbionts in mature oocytes decreased. Further study showed that NlSLC26A10 might result in decreased juvenile hormone level and vitellogenin expression. These results indicate that NlSLC26A10 plays an essential role in the reproduction of N. lugens.
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Berg P, Svendsen SL, Hoang TTL, Praetorius HA, Sorensen MV, Leipziger J. Impaired renal HCO 3 - secretion in CFTR deficient mice causes metabolic alkalosis during chronic base-loading. Acta Physiol (Oxf) 2021; 231:e13591. [PMID: 33270356 DOI: 10.1111/apha.13591] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 11/27/2020] [Accepted: 11/27/2020] [Indexed: 12/11/2022]
Abstract
AIM Cystic fibrosis patients have an increased risk of developing metabolic alkalosis presumably as a result of altered renal HCO3 - handling. In this study, we directly assess the kidneys' ability to compensate for a chronic base-load in the absence of functional CFTR. METHODS Comprehensive urine and blood acid-base analyses were done in anaesthetized WT mice or mice lacking either CFTR or pendrin, with or without 7 days of oral NaHCO3 loading. The in vivo experiments were complemented by a combination of immunoblotting and experiments with perfused isolated mouse cortical collecting ducts (CCD). RESULTS Base-loaded WT mice maintained acid-base homeostasis by elevating urinary pH and HCO3 - excretion and decreasing urinary net acid excretion. In contrast, pendrin KO mice and CFTR KO mice were unable to increase urinary pH and HCO3 - excretion and unable to decrease urinary net acid excretion sufficiently and thus developed metabolic alkalosis in response to the same base-load. The expression of pendrin was increased in response to the base-load in WT mice with a paralleled increased pendrin function in the perfused CCD. In CFTR KO mice, 7 days of base-loading did not upregulate pendrin expression and apical Cl- /HCO3 - exchange function was strongly blunted in the CCD. CONCLUSION CFTR KO mice develop metabolic alkalosis during a chronic base-load because they are unable to sufficiently elevate renal HCO3 - excretion. This can be explained by markedly reduced pendrin function in the absence of CFTR.
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Affiliation(s)
- Peder Berg
- Department of Biomedicine, Physiology Faculty of Health Aarhus University Aarhus C Denmark
| | - Samuel L. Svendsen
- Department of Biomedicine, Physiology Faculty of Health Aarhus University Aarhus C Denmark
| | - Thi Thuy Linh Hoang
- Department of Biomedicine, Physiology Faculty of Health Aarhus University Aarhus C Denmark
| | - Helle A. Praetorius
- Department of Biomedicine, Physiology Faculty of Health Aarhus University Aarhus C Denmark
| | - Mads V. Sorensen
- Department of Biomedicine, Physiology Faculty of Health Aarhus University Aarhus C Denmark
| | - Jens Leipziger
- Department of Biomedicine, Physiology Faculty of Health Aarhus University Aarhus C Denmark
- Aarhus Institute of Advanced Studies Aarhus University Aarhus C Denmark
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The electrogenic sodium bicarbonate cotransporter and its roles in the myocardial ischemia-reperfusion induced cardiac diseases. Life Sci 2021; 270:119153. [PMID: 33539911 DOI: 10.1016/j.lfs.2021.119153] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 01/06/2021] [Accepted: 01/22/2021] [Indexed: 12/19/2022]
Abstract
Cardiac tissue ischemia/hypoxia increases glycolysis and lactic acid accumulation in cardiomyocytes, leading to intracellular metabolic acidosis. Sodium bicarbonate cotransporters (NBCs) play a vital role in modulating intracellular pH and maintaining sodium ion concentrations in cardiomyocytes. Cardiomyocytes mainly express electrogenic sodium bicarbonate cotransporter (NBCe1), which has been demonstrated to participate in myocardial ischemia/reperfusion (I/R) injury. This review outlines the structural and functional properties of NBCe1, summarizes the signaling pathways and factors that may regulate the activity of NBCe1, and reviews the roles of NBCe1 in the pathogenesis of I/R-induced cardiac diseases. Further studies revealing the regulatory mechanisms of NBCe1 activity should provide novel therapeutic targets for preventing I/R-induced cardiac diseases.
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8
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Cuthbert JJ, Bhandari S, Clark AL. Hypochloraemia in Patients with Heart Failure: Causes and Consequences. Cardiol Ther 2020; 9:333-347. [PMID: 32772346 PMCID: PMC7584710 DOI: 10.1007/s40119-020-00194-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Indexed: 12/19/2022] Open
Abstract
Hypochloraemia is a common electrolyte abnormality in patients with heart failure (HF). It has a strong association with adverse outcome regardless of HF phenotype and independent of other prognostic markers. How hypochloraemia develops in a patient with HF and how it might influence outcome are not clear, and in this review we explore the possible mechanisms. Patients with HF and hypochloraemia almost invariably take higher doses of loop diuretic than patients with normal chloride levels. However, renal chloride and bicarbonate homeostasis are closely linked, and the latter may be influenced by neurohormonal activation: it is likely that the etiology of hypochloraemia in patients with HF is multifactorial and due to more than just diuretic-induced urinary losses. There are multiple proposed mechanisms by which low chloride concentrations may lead to an adverse outcome in patients with HF: by increasing renin release; by a stimulatory effect on the with-no-lysine kinases which might increase renal sodium-chloride co-transporter activity; and by an adverse effect on myocardial conduction and contractility. None of these proposed mechanisms are proven in humans with HF. However, if true, it might suggest that hypochloraemia is a therapeutic target that might be amenable to treatment with acetazolamide or chloride supplementation.
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Affiliation(s)
- Joseph J Cuthbert
- Department of Academic Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK.
| | - Sunil Bhandari
- Department of Academic Nephrology, Hull University Teaching Hospitals NHS Trust and Hull York Medical School, Anlaby Road, Kingston upon Hull, HU3 2JZ, UK
| | - Andrew L Clark
- Department of Academic Cardiology, Hull York Medical School, Hull and East Yorkshire Medical Research and Teaching Centre, Castle Hill Hospital, Cottingham, Kingston upon Hull, HU16 5JQ, UK
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Human Sperm Capacitation Involves the Regulation of the Tyr-Phosphorylation Level of the Anion Exchanger 1 (AE1). Int J Mol Sci 2020; 21:ijms21114063. [PMID: 32517126 PMCID: PMC7311965 DOI: 10.3390/ijms21114063] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/02/2020] [Accepted: 06/03/2020] [Indexed: 12/22/2022] Open
Abstract
Bicarbonate uptake is one of the early steps of capacitation, but the identification of proteins regulating anion fluxes remains elusive. The aim of this study is to investigate the role of sperm solute carrier 4 (SLC4) A1 (spAE1) in the capacitation process. The expression, location, and tyrosine-phosphorylation (Tyr-P) level of spAE1 were assessed. Thereby, it was found that 4,4′-Diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS), an SLC4 family channel blocker, inhibited capacitation in a dose-dependent manner by decreasing acrosome reaction (ARC% 24.5 ± 3.3 vs. 64.9 ± 4.3, p < 0.05) and increasing the percentage of not viable cells (NVC%), comparable to the inhibition by I-172, a cystic fibrosis transmembrane conductance regulator (CFTR) blocker (AR% 30.5 ± 4.4 and NVC% 18.6 ± 2.2). When used in combination, a synergistic inhibitory effect was observed with a remarkable increase of the percentage of NVC (45.3 ± 4.1, p < 0.001). spAE1 was identified in sperm membrane as a substrate for Tyr-protein kinases Lyn and Syk, which were identified as both soluble and membrane-bound pools. spAE1-Tyr-P level increased in the apical region of sperm under capacitating conditions and was negatively affected by I-172 or DIDS, and, to a far greater extent, by a combination of both. In conclusion, we demonstrated that spAE1 is expressed in sperm membranes and it is phosphorylated by Syk, but above all by Lyn on Tyr359, which are involved in sperm viability and capacitation.
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10
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Bernardino RL, Carrageta DF, Sousa M, Alves MG, Oliveira PF. pH and male fertility: making sense on pH homeodynamics throughout the male reproductive tract. Cell Mol Life Sci 2019; 76:3783-3800. [PMID: 31165202 PMCID: PMC11105638 DOI: 10.1007/s00018-019-03170-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 04/24/2019] [Accepted: 05/29/2019] [Indexed: 02/07/2023]
Abstract
In the male reproductive tract, ionic equilibrium is essential to maintain normal spermatozoa production and, hence, the reproductive potential. Among the several ions, HCO3- and H+ have a central role, mainly due to their role on pH homeostasis. In the male reproductive tract, the major players in pH regulation and homeodynamics are carbonic anhydrases (CAs), HCO3- membrane transporters (solute carrier 4-SLC4 and solute carrier 26-SLC26 family transporters), Na+-H+ exchangers (NHEs), monocarboxylate transporters (MCTs) and voltage-gated proton channels (Hv1). CAs and these membrane transporters are widely distributed throughout the male reproductive tract, where they play essential roles in the ionic balance of tubular fluids. CAs are the enzymes responsible for the production of HCO3- which is then transported by membrane transporters to ensure the maturation, storage, and capacitation of the spermatozoa. The transport of H+ is carried out by NHEs, Hv1, and MCTs and is essential for the electrochemical balance and for the maintenance of the pH within the physiological limits along the male reproductive tract. Alterations in HCO3- production and transport of ions have been associated with some male reproductive dysfunctions. Herein, we present an up-to-date review on the distribution and role of the main intervenient on pH homeodynamics in the fluids throughout the male reproductive tract. In addition, we discuss their relevance for the establishment of the male reproductive potential.
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Affiliation(s)
- Raquel L Bernardino
- Laboratory of Cell Biology, Department of Microscopy, Institute of Biomedical Sciences Abel Salazar and Unit for Multidisciplinary Research in Biomedicine, University of Porto, Porto, Portugal
| | - David F Carrageta
- Laboratory of Cell Biology, Department of Microscopy, Institute of Biomedical Sciences Abel Salazar and Unit for Multidisciplinary Research in Biomedicine, University of Porto, Porto, Portugal
| | - Mário Sousa
- Laboratory of Cell Biology, Department of Microscopy, Institute of Biomedical Sciences Abel Salazar and Unit for Multidisciplinary Research in Biomedicine, University of Porto, Porto, Portugal
| | - Marco G Alves
- Institute of Biomedical Sciences Abel Salazar and Unit for Multidisciplinary Research in Biomedicine, University of Porto, Porto, Portugal
| | - Pedro F Oliveira
- Laboratory of Cell Biology, Department of Microscopy, Institute of Biomedical Sciences Abel Salazar and Unit for Multidisciplinary Research in Biomedicine, University of Porto, Porto, Portugal.
- i3S-Institute for Innovation and Health Research, University of Porto, Porto, Portugal.
- Department of Genetics, Faculty of Medicine, University of Porto, Porto, Portugal.
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Seidler U, Nikolovska K. Slc26 Family of Anion Transporters in the Gastrointestinal Tract: Expression, Function, Regulation, and Role in Disease. Compr Physiol 2019; 9:839-872. [DOI: 10.1002/cphy.c180027] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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12
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Mukaibo T, Munemasa T, George AT, Tran DT, Gao X, Herche JL, Masaki C, Shull GE, Soleimani M, Melvin JE. The apical anion exchanger Slc26a6 promotes oxalate secretion by murine submandibular gland acinar cells. J Biol Chem 2018; 293:6259-6268. [PMID: 29530983 PMCID: PMC5925796 DOI: 10.1074/jbc.ra118.002378] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/08/2018] [Indexed: 12/15/2022] Open
Abstract
The solute carrier family 26 (SLC26) gene family encodes at least 10 different anion exchangers. SLC26 member 6 (SLC26A6 or CFEX/PAT-1) and the cystic fibrosis transmembrane conductance regulator (CFTR) co-localize to the apical membrane of pancreatic duct cells, where they act in concert to drive HCO3- and fluid secretion. In contrast, in the small intestine, SLC26A6 serves as the major pathway for oxalate secretion. However, little is known about the function of Slc26a6 in murine salivary glands. Here, RNA sequencing-based transcriptional profiling and Western blots revealed that Slc26a6 is highly expressed in mouse submandibular and sublingual salivary glands. Slc26a6 localized to the apical membrane of salivary gland acinar cells with no detectable immunostaining in the ducts. CHO-K1 cells transfected with mouse Slc26a6 exchanged Cl- for oxalate and HCO3-, whereas two other anion exchangers known to be expressed in salivary gland acinar cells, Slc4a4 and Slc4a9, mediated little, if any, Cl-/oxalate exchange. Of note, both Cl-/oxalate exchange and Cl-/HCO3- exchange were significantly reduced in acinar cells isolated from the submandibular glands of Slc26a6-/- mice. Oxalate secretion in submandibular saliva also decreased significantly in Slc26a6-/- mice, but HCO3- secretion was unaffected. Taken together, our findings indicate that Slc26a6 is located at the apical membrane of salivary gland acinar cells, where it mediates Cl-/oxalate exchange and plays a critical role in the secretion of oxalate into saliva.
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Affiliation(s)
- Taro Mukaibo
- From the Secretory Mechanisms and Dysfunctions Section and
- the Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan
| | - Takashi Munemasa
- From the Secretory Mechanisms and Dysfunctions Section and
- the Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan
| | - Alvin T George
- From the Secretory Mechanisms and Dysfunctions Section and
| | - Duy T Tran
- Biological Chemistry Section, NIDCR, National Institutes of Health, Bethesda, Maryland 20892
| | - Xin Gao
- From the Secretory Mechanisms and Dysfunctions Section and
- the Joint Institute for Food Safety and Applied Nutrition, University of Maryland, College Park, Maryland 20742, and
| | - Jesse L Herche
- From the Secretory Mechanisms and Dysfunctions Section and
| | - Chihiro Masaki
- the Department of Oral Reconstruction and Rehabilitation, Kyushu Dental University, Kitakyushu, Fukuoka 803-8580, Japan
| | - Gary E Shull
- Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267
| | | | - James E Melvin
- From the Secretory Mechanisms and Dysfunctions Section and
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13
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Li JW, Yuan K, Shang SC, Guo Y. A safer hypoglycemic agent for type 2 diabetes—Berberine organic acid salt. J Funct Foods 2017. [DOI: 10.1016/j.jff.2017.09.031] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
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14
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Orentas RJ, Sindiri S, Duris C, Wen X, He J, Wei JS, Jarzembowski J, Khan J. Paired Expression Analysis of Tumor Cell Surface Antigens. Front Oncol 2017; 7:173. [PMID: 28871274 PMCID: PMC5566986 DOI: 10.3389/fonc.2017.00173] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 07/31/2017] [Indexed: 01/15/2023] Open
Abstract
Adoptive immunotherapy with antibody-based therapy or with T cells transduced to express chimeric antigen receptors (CARs) is useful to the extent that the cell surface membrane protein being targeted is not expressed on normal tissues. The most successful CAR-based (anti-CD19) or antibody-based therapy (anti-CD20) in hematologic malignancies has the side effect of eliminating the normal B cell compartment. Targeting solid tumors may not provide a similar expendable marker. Beyond antibody to Her2/NEU and EGFR, very few antibody-based and no CAR-based therapies have seen broad clinical application for solid tumors. To expand the way in which the surfaceome of solid tumors can be analyzed, we created an algorithm that defines the pairwise relative overexpression of surface antigens. This enables the development of specific immunotherapies that require the expression of two discrete antigens on the surface of the tumor target. This dyad analysis was facilitated by employing the Hotelling’s T-squared test (Hotelling–Lawley multivariate analysis of variance) for two independent variables in comparison to a third constant entity (i.e., gene expression levels in normal tissues). We also present a unique consensus scoring mechanism for identifying transcripts that encode cell surface proteins. The unique application of our bioinformatics processing pipeline and statistical tools allowed us to compare the expression of two membrane protein targets as a pair, and to propose a new strategy based on implementing immunotherapies that require both antigens to be expressed on the tumor cell surface to trigger therapeutic effector mechanisms. Specifically, we found that, for MYCN amplified neuroblastoma, pairwise expression of ACVR2B or anaplastic lymphoma kinase (ALK) with GFRA3, GFRA2, Cadherin 24, or with one another provided the strongest hits. For MYCN, non-amplified stage 4 neuroblastoma, neurotrophic tyrosine kinase 1, or ALK paired with GFRA2, GFRA3, SSK1, GPR173, or with one another provided the most promising paired-hits. We propose that targeting these markers together would increase the specificity and thereby the safety of CAR-based therapy for neuroblastoma.
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Affiliation(s)
- Rimas J Orentas
- Lentigen Technology, Inc., a Miltenyi Biotec Company, Gaithersburg, MD, United States
| | - Sivasish Sindiri
- Genetics Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States
| | - Christine Duris
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Xinyu Wen
- Genetics Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States
| | - Jianbin He
- Genetics Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States
| | - Jun S Wei
- Genetics Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States
| | - Jason Jarzembowski
- Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Javed Khan
- Genetics Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Bethesda, MD, United States
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15
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Ferreira JP, Girerd N, Duarte K, Coiro S, McMurray JJV, Dargie HJ, Pitt B, Dickstein K, Testani JM, Zannad F, Rossignol P. Serum Chloride and Sodium Interplay in Patients With Acute Myocardial Infarction and Heart Failure With Reduced Ejection Fraction. Circ Heart Fail 2017; 10:CIRCHEARTFAILURE.116.003500. [DOI: 10.1161/circheartfailure.116.003500] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 01/03/2017] [Indexed: 01/24/2023]
Abstract
Background—
Serum chloride levels were recently found to be independently associated with mortality in heart failure (HF).
Methods and Results—
We investigated the relationship between serum chloride and clinical outcomes in 7195 subjects with acute myocardial infarction complicated by reduced left ventricular function and HF. The studied outcomes were all-cause mortality, cardiovascular mortality, and hospitalization for HF. Both chloride and sodium had a nonlinear association with the studied outcomes (
P
<0.05 for linearity). Patients in the lowest chloride tertile (chloride ≤100) were older, had more comorbidities, and had lower sodium levels (
P
<0.05 for all). Serum chloride showed a significant interaction with sodium with regard to all studied outcomes (
P
for interaction <0.05 for all). The lowest chloride tertile (≤100 mmol/L) was associated with increased mortality rates in the context of lower sodium (≤138 mmol/L; adjusted hazard ratio [95% confidence interval] for all-cause mortality=1.42 (1.14–1.77);
P
=0.002), whereas in the context of higher sodium levels (>141 mmol/L), the association with mortality was lost. Spline-transformed chloride and its interaction with sodium did not add significant prognostic information on top of other well-established prognostic variables (
P
>0.05 for all outcomes).
Conclusions—
In post–myocardial infarction with systolic dysfunction and HF, low serum chloride was associated with mortality (but not hospitalization for HF) in the setting of lower sodium. Overall, chloride and its interaction with sodium did not add clinically relevant prognostic information on top of other well-established prognostic variables. Taken together, these data support an integrated and critical consideration of chloride and sodium interplay.
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Affiliation(s)
- João Pedro Ferreira
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Nicolas Girerd
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Kevin Duarte
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Stefano Coiro
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - John J. V. McMurray
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Henry J. Dargie
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Bertram Pitt
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Kenneth Dickstein
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Jeffrey M. Testani
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Faiez Zannad
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
| | - Patrick Rossignol
- From the INSERM, Centre d’Investigations Cliniques Plurithématique 1433, INSERM U1116, Université de Lorraine, CHRU de Nancy, F-CRIN INI-CRCT, France (J.P.F., N.G., K.D., S.C., F.Z., P.R.); Department of Physiology and Cardiothoracic Surgery, Cardiovascular Research and Development Unit, Faculty of Medicine, University of Porto, Portugal (J.P.F.); Division of Cardiology, School of Medicine, University of Perugia, Italy (S.C.); British Heart Foundation Cardiovascular Research Centre (J.J.V.M.) and
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16
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The Role of Epithelial Sodium Channel ENaC and the Apical Cl-/HCO3- Exchanger Pendrin in Compensatory Salt Reabsorption in the Setting of Na-Cl Cotransporter (NCC) Inactivation. PLoS One 2016; 11:e0150918. [PMID: 26963391 PMCID: PMC4786216 DOI: 10.1371/journal.pone.0150918] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 02/18/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The absence of NCC does not cause significant salt wasting in NCC deficient mice under basal conditions. We hypothesized that ENaC and pendrin play important roles in compensatory salt absorption in the setting of NCC inactivation, and their inhibition and/or downregulation can cause significant salt wasting in NCC KO mice. METHODS WT and NCC KO mice were treated with a daily injection of either amiloride, an inhibitor of ENaC, or acetazolamide (ACTZ), a blocker of salt and bicarbonate reabsorption in the proximal tubule and an inhibitor of carbonic anhydrases in proximal tubule and intercalated cells, or a combination of acetazolamide plus amiloride for defined durations. Animals were subjected to daily balance studies. At the end of treatment, kidneys were harvested and examined. Blood samples were collected for electrolytes and acid base analysis. RESULTS Amiloride injection significantly increased the urine output (UO) in NCC KO mice (from 1.3 ml/day before to 2.5 ml/day after amiloride, p<0.03, n = 4) but caused only a slight change in UO in WT mice (p>0.05). The increase in UO in NCC KO mice was associated with a significant increase in sodium excretion (from 0.25 mmol/24 hrs at baseline to 0.35 mmol/24 hrs after amiloride injection, p<0.05, n = 4). Daily treatment with ACTZ for 6 days resulted in >80% reduction of kidney pendrin expression in both WT and NCC KO mice. However, ACTZ treatment noticeably increased urine output and salt excretion only in NCC KO mice (with urine output increasing from a baseline of 1.1 ml/day to 2.3 ml/day and sodium excretion increasing from 0.22 mmole/day before to 0.31 mmole/day after ACTZ) in NCC KO mice; both parameters were significantly higher than in WT mice. Western blot analysis demonstrated significant enhancement in ENaC expression in medulla and cortex of NCC KO and WT mice in response to ACTZ injection for 6 days, and treatment with amiloride in ACTZ-pretreated mice caused a robust increase in salt excretion in both NCC KO and WT mice. Pendrin KO mice did not display a significant increase in urine output or salt excretion after treatment with amiloride or ACTZ. CONCLUSION 1. ENaC plays an important role in salt reabsorption in NCC KO mice. 2. NCC contributes to compensatory salt reabsorption in the setting of carbonic anhydrase inhibition, which is associated with increased delivery of salt from the proximal tubule and the down regulation of pendrin. 3. ENaC is upregulated by ACTZ treatment and its inhibition by amiloride causes significant diuresis in NCC KO and WT mice. Despite being considered mild agents individually, we propose that the combination of acetazolamide and amiloride in the setting of NCC inhibition (i.e., hydrochlorothiazide) will be a powerful diuretic regimen.
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17
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Sohrabi-Jahromi S, Marashi SA, Kalantari S. A kidney-specific genome-scale metabolic network model for analyzing focal segmental glomerulosclerosis. Mamm Genome 2016; 27:158-67. [PMID: 26923795 DOI: 10.1007/s00335-016-9622-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 01/31/2016] [Indexed: 01/02/2023]
Abstract
Focal Segmental Glomerulosclerosis (FSGS) is a type of nephrotic syndrome which accounts for 20 and 40 % of such cases in children and adults, respectively. The high prevalence of FSGS makes it the most common primary glomerular disorder causing end-stage renal disease. Although the pathogenesis of this disorder has been widely investigated, the exact mechanism underlying this disease is still to be discovered. Current therapies seek to stop the progression of FSGS and often fail to cure the patients since progression to end-stage renal failure is usually inevitable. In the present work, we use a kidney-specific metabolic network model to study FSGS. The model was obtained by merging two previously published kidney-specific metabolic network models. The validity of the new model was checked by comparing the inactivating reaction genes identified in silico to the list of kidney disease implicated genes. To model the disease state, we used a complete list of FSGS metabolic biomarkers extracted from transcriptome and proteome profiling of patients as well as genetic deficiencies known to cause FSGS. We observed that some specific pathways including chondroitin sulfate degradation, eicosanoid metabolism, keratan sulfate biosynthesis, vitamin B6 metabolism, and amino acid metabolism tend to show variations in FSGS model compared to healthy kidney. Furthermore, we computationally searched for the potential drug targets that can revert the diseased metabolic state to the healthy state. Interestingly, only one drug target, N-acetylgalactosaminidase, was found whose inhibition could alter cellular metabolism towards healthy state.
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Affiliation(s)
| | - Sayed-Amir Marashi
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran.
| | - Shiva Kalantari
- Chronic Kidney Disease Research Center (CKDRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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18
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Jalali R, Zandieh-Doulabi B, DenBesten PK, Seidler U, Riederer B, Wedenoja S, Micha D, Bronckers ALJJ. Slc26a3/Dra and Slc26a6 in Murine Ameloblasts. J Dent Res 2015; 94:1732-9. [PMID: 26394631 DOI: 10.1177/0022034515606873] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Formation of apatite crystals during enamel development generates protons. To sustain mineral accretion, maturation ameloblasts need to buffer these protons. The presence of cytosolic carbonic anhydrases, the basolateral Na(+) bicarbonate cotransporter Nbce1, and the basolateral anion exchanger Ae2a,b in maturation ameloblasts suggests that these cells secrete bicarbonates into the forming enamel, but it is unknown by which mechanism. Solute carrier (Slc) family 26A encodes different anion exchangers that exchange Cl(-)/HCO3 (-), including Slc26a3/Dra, Slc26a6/Pat-1, and Slc26a4/pendrin. Previously, we showed that pendrin is expressed in ameloblasts but is not critical for enamel formation. In this study, we tested the hypothesis that maturation ameloblasts express Dra and Slc26a6 to secrete bicarbonate into the enamel space in exchange for Cl(-). Real-time polymerase chain reaction detected mRNA transcripts for Dra and Slc26a6 in mouse incisor enamel organs, and Western blotting confirmed their translation into protein. Both isoforms were immunolocalized in ameloblasts, principally at maturation stage. Mice with null mutation of either Dra or Slc26a6 had a normal dental or skeletal phenotype without changes in mineral density, as measured by micro-computed tomography. In enamel organs of Slc26a6-null mice, Dra and pendrin protein levels were both elevated by 52% and 55%, respectively. The amount of Slc26a6 protein was unchanged in enamel organs of Ae2a,b- and Cftr-null mice but reduced in Dra-null mice by 36%. Our data show that ameloblasts express Dra, pendrin, or Slc26a6 but each of these separately is not critical for formation of dental enamel. The data suggest that in ameloblasts, Slc26a isoforms can functionally compensate for one another.
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Affiliation(s)
- R Jalali
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, University of Amsterdam, and MOVE Research Institute, VU University Amsterdam, Amsterdam, Netherlands
| | - B Zandieh-Doulabi
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, University of Amsterdam, and MOVE Research Institute, VU University Amsterdam, Amsterdam, Netherlands
| | - P K DenBesten
- Department of Oral Sciences, University of California, San Francisco, CA, USA
| | - U Seidler
- Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - B Riederer
- Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - S Wedenoja
- Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland
| | - D Micha
- Department of Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, Netherlands
| | - A L J J Bronckers
- Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam, University of Amsterdam, and MOVE Research Institute, VU University Amsterdam, Amsterdam, Netherlands
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19
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Abstract
Cation-coupled HCO3(-) transport was initially identified in the mid-1970s when pioneering studies showed that acid extrusion from cells is stimulated by CO2/HCO3(-) and associated with Na(+) and Cl(-) movement. The first Na(+)-coupled bicarbonate transporter (NCBT) was expression-cloned in the late 1990s. There are currently five mammalian NCBTs in the SLC4-family: the electrogenic Na,HCO3-cotransporters NBCe1 and NBCe2 (SLC4A4 and SLC4A5 gene products); the electroneutral Na,HCO3-cotransporter NBCn1 (SLC4A7 gene product); the Na(+)-driven Cl,HCO3-exchanger NDCBE (SLC4A8 gene product); and NBCn2/NCBE (SLC4A10 gene product), which has been characterized as an electroneutral Na,HCO3-cotransporter or a Na(+)-driven Cl,HCO3-exchanger. Despite the similarity in amino acid sequence and predicted structure among the NCBTs of the SLC4-family, they exhibit distinct differences in ion dependency, transport function, pharmacological properties, and interactions with other proteins. In epithelia, NCBTs are involved in transcellular movement of acid-base equivalents and intracellular pH control. In nonepithelial tissues, NCBTs contribute to intracellular pH regulation; and hence, they are crucial for diverse tissue functions including neuronal discharge, sensory neuron development, performance of the heart, and vascular tone regulation. The function and expression levels of the NCBTs are generally sensitive to intracellular and systemic pH. Animal models have revealed pathophysiological roles of the transporters in disease states including metabolic acidosis, hypertension, visual defects, and epileptic seizures. Studies are being conducted to understand the physiological consequences of genetic polymorphisms in the SLC4-members, which are associated with cancer, hypertension, and drug addiction. Here, we describe the current knowledge regarding the function, structure, and regulation of the mammalian cation-coupled HCO3(-) transporters of the SLC4-family.
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Affiliation(s)
- Christian Aalkjaer
- Department of Biomedicine, and the Water and Salt Research Center, Aarhus University, Aarhus, Denmark; Department of Physiology, Emory University School of Medicine, Atlanta, USA
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Bhasin B, Ürekli HM, Atta MG. Primary and secondary hyperoxaluria: Understanding the enigma. World J Nephrol 2015; 4:235-244. [PMID: 25949937 PMCID: PMC4419133 DOI: 10.5527/wjn.v4.i2.235] [Citation(s) in RCA: 120] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 08/29/2014] [Accepted: 02/09/2015] [Indexed: 02/05/2023] Open
Abstract
Hyperoxaluria is characterized by an increased urinary excretion of oxalate. Primary and secondary hyperoxaluria are two distinct clinical expressions of hyperoxaluria. Primary hyperoxaluria is an inherited error of metabolism due to defective enzyme activity. In contrast, secondary hyperoxaluria is caused by increased dietary ingestion of oxalate, precursors of oxalate or alteration in intestinal microflora. The disease spectrum extends from recurrent kidney stones, nephrocalcinosis and urinary tract infections to chronic kidney disease and end stage renal disease. When calcium oxalate burden exceeds the renal excretory ability, calcium oxalate starts to deposit in various organ systems in a process called systemic oxalosis. Increased urinary oxalate levels help to make the diagnosis while plasma oxalate levels are likely to be more accurate when patients develop chronic kidney disease. Definitive diagnosis of primary hyperoxaluria is achieved by genetic studies and if genetic studies prove inconclusive, liver biopsy is undertaken to establish diagnosis. Diagnostic clues pointing towards secondary hyperoxaluria are a supportive dietary history and tests to detect increased intestinal absorption of oxalate. Conservative treatment for both types of hyperoxaluria includes vigorous hydration and crystallization inhibitors to decrease calcium oxalate precipitation. Pyridoxine is also found to be helpful in approximately 30% patients with primary hyperoxaluria type 1. Liver-kidney and isolated kidney transplantation are the treatment of choice in primary hyperoxaluria type 1 and type 2 respectively. Data is scarce on role of transplantation in primary hyperoxaluria type 3 where there are no reports of end stage renal disease so far. There are ongoing investigations into newer modalities of diagnosis and treatment of hyperoxaluria. Clinical differentiation between primary and secondary hyperoxaluria and further between the types of primary hyperoxaluria is very important because of implications in treatment and diagnosis. Hyperoxaluria continues to be a challenging disease and a high index of clinical suspicion is often the first step on the path to accurate diagnosis and management.
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21
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Soleimani M. The multiple roles of pendrin in the kidney. Nephrol Dial Transplant 2014; 30:1257-66. [PMID: 25281699 DOI: 10.1093/ndt/gfu307] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2014] [Accepted: 08/25/2014] [Indexed: 12/30/2022] Open
Abstract
The [Formula: see text] exchanger pendrin (SLC26A4, PDS) is located on the apical membrane of B-intercalated cells in the kidney cortical collecting duct and the connecting tubules and mediates the secretion of bicarbonate and the reabsorption of chloride. Given its dual function of bicarbonate secretion and chloride reabsorption in the distal tubules, it was thought that pendrin plays important roles in systemic acid-base balance and electrolyte and vascular volume homeostasis under basal conditions. Mice with the genetic deletion of pendrin or humans with inactivating mutations in PDS gene, however, do not display excessive salt and fluid wasting or altered blood pressure under baseline conditions. Very recent reports have unmasked the basis of incongruity between the mild phenotype in mutant mice and the role of pendrin as an important player in salt reabsorption in the distal tubule. These studies demonstrate that pendrin and the Na-Cl cotransporter (NCC; SLC12A3) cross compensate for the loss of each other, therefore masking the role that each transporter plays in salt reabsorption under baseline conditions. In addition, pendrin regulates calcium reabsorption in the distal tubules. Furthermore, combined deletion of pendrin and NCC not only causes severe volume depletion but also results in profound calcium wasting and luminal calcification in medullary collecting ducts. Based on studies in pathophysiological states and the examination of genetically engineered mouse models, the evolving picture points to important roles for pendrin (SLC26A4) in kidney physiology and in disease states. This review summarizes recent advances in the characterization of pendrin and the multiple roles it plays in the kidney, with emphasis on its essential roles in several diverse physiological processes, including chloride homeostasis, vascular volume and blood pressure regulation, calcium excretion and kidney stone formation.
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Affiliation(s)
- Manoocher Soleimani
- Center on Genetics of Transport and Epithelial Biology, University of Cincinnati, Cincinnati, OH, USA Research Services, Veterans Affairs Medical Center, Cincinnati, OH, USA Department of Medicine, University of Cincinnati, Cincinnati, OH, USA
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22
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Nishigaki T, José O, González-Cota AL, Romero F, Treviño CL, Darszon A. Intracellular pH in sperm physiology. Biochem Biophys Res Commun 2014; 450:1149-58. [PMID: 24887564 PMCID: PMC4146485 DOI: 10.1016/j.bbrc.2014.05.100] [Citation(s) in RCA: 125] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 05/22/2014] [Indexed: 10/25/2022]
Abstract
Intracellular pH (pHi) regulation is essential for cell function. Notably, several unique sperm ion transporters and enzymes whose elimination causes infertility are either pHi dependent or somehow related to pHi regulation. Amongst them are: CatSper, a Ca(2+) channel; Slo3, a K(+) channel; the sperm-specific Na(+)/H(+) exchanger and the soluble adenylyl cyclase. It is thus clear that pHi regulation is of the utmost importance for sperm physiology. This review briefly summarizes the key components involved in pHi regulation, their characteristics and participation in fundamental sperm functions such as motility, maturation and the acrosome reaction.
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Affiliation(s)
- Takuya Nishigaki
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, 62210, Mexico
| | - Omar José
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, 62210, Mexico
| | - Ana Laura González-Cota
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, 62210, Mexico
| | - Francisco Romero
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, 62210, Mexico
| | - Claudia L Treviño
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, 62210, Mexico
| | - Alberto Darszon
- Departamento de Genética del Desarrollo y Fisiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos, 62210, Mexico.
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Li J, Xia F, Reithmeier RAF. N-glycosylation and topology of the human SLC26 family of anion transport membrane proteins. Am J Physiol Cell Physiol 2014; 306:C943-60. [PMID: 24647542 DOI: 10.1152/ajpcell.00030.2014] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The human solute carrier (SLC26) family of anion transporters consists of 10 members (SLCA1-11, SLCA10 being a pseudogene) that encode membrane proteins containing ~12 transmembrane (TM) segments with putative N-glycosylation sites (-NXS/T-) in extracellular loops and a COOH-terminal cytosolic STAS domain. All 10 members of the human SLC26 family, FLAG-tagged at the NH2 terminus, were transiently expressed in HEK-293 cells. While most proteins were observed to contain both high-mannose and complex oligosaccharides, SLC26A2 was mainly in the complex form, SLC26A4 in the high-mannose form, and SLC26A8 was not N-glycosylated. Mutation of the putative N-glycosylation sites showed that most members contain multiple N-glycosylation sites in the second extracytosolic (EC) loop, except SLC26A11, which was N-glycosylated in EC loop 4. Immunofluorescence staining of permeabilized cells localized the proteins to the plasma membrane and the endoplasmic reticulum, with SLC26A2 highly localized to the plasma membrane. N-glycosylation was not a necessary requirement for cell surface expression as the localization of nonglycosylated proteins was similar to their wild-type counterparts, although a lower level of cell-surface biotinylation was observed. No immunostaining of intact cells was observed for any SLC26 members, demonstrating that the NH2-terminal FLAG tag was located in the cytosol. Topological models of the SLC26 proteins that contain an even number of transmembrane segments with both the NH2 and COOH termini located in the cytosol and utilized N-glycosylation sites defining the positions of two EC loops are presented.
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Affiliation(s)
- Jing Li
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
| | - Fan Xia
- Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
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Zahedi K, Barone S, Xu J, Soleimani M. Potentiation of the effect of thiazide derivatives by carbonic anhydrase inhibitors: molecular mechanisms and potential clinical implications. PLoS One 2013; 8:e79327. [PMID: 24260196 PMCID: PMC3832474 DOI: 10.1371/journal.pone.0079327] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 09/29/2013] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Carbonic anhydrase inhibitors (CAI) are mild diuretics, hence not widely used in fluid overloaded states. They are however the treatment of choice for certain non-kidney conditions. Thiazides, specific inhibitors of Na-Cl cotransport (NCC), are mild agents and the most widely used diuretics in the world for control of mild hypertension. HYPOTHESIS In addition to inhibiting the salt reabsorption in the proximal tubule, CAIs down-regulate pendrin, therefore leaving NCC as the major salt absorbing transporter in the distal nephron, and hence allowing for massive diuresis by the inhibitors of NCC in the setting of increased delivery of salt from the proximal tubule. EXPERIMENTAL PROTOCOLS AND RESULTS Daily treatment of rats with acetazolamide (ACTZ), a known CAI, for 10 days caused mild diuresis whereas daily treatment with hydrochlorothiazide (HCTZ) for 4 days caused hardly any diuresis. However, treatment of rats that were pretreated with ACTZ for 6 days with a combination of ACTZ plus HCTZ for 4 additional days increased the urine output by greater than 2 fold (p<0.001, n = 5) compared to ACTZ-treated animals. Sodium excretion increased by 80% in the ACTZ plus HCTZ group and animals developed significant volume depletion, metabolic alkalosis and pre-renal failure. Molecular studies demonstrated ∼75% reduction in pendrin expression by ACTZ. The increased urine output in ACTZ/HCTZ treated rats was associated with a significant reduction in urine osmolality and reduced membrane localization of AQP-2 (aquaporin2). CONCLUSIONS These results indicate that ACTZ down-regulates pendrin expression and leaves NCC as the major salt absorbing transporter in the distal nephron in the setting of increased delivery of salt from the proximal tubule. Despite being considered mild agents individually, we propose that the combination of ACTZ and HCTZ is a powerful diuretic regimen.
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Affiliation(s)
- Kamyar Zahedi
- Center on Genetics of Transport and the Department of Medicine, University of Cincinnati, Research Services, Veterans Affairs Medical Center, Cincinnati, Ohio
| | - Sharon Barone
- Center on Genetics of Transport and the Department of Medicine, University of Cincinnati, Research Services, Veterans Affairs Medical Center, Cincinnati, Ohio
| | - Jie Xu
- Center on Genetics of Transport and the Department of Medicine, University of Cincinnati, Research Services, Veterans Affairs Medical Center, Cincinnati, Ohio
| | - Manoocher Soleimani
- Center on Genetics of Transport and the Department of Medicine, University of Cincinnati, Research Services, Veterans Affairs Medical Center, Cincinnati, Ohio
- * E-mail:
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25
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Miller J, Chi T, Kapahi P, Kahn AJ, Kim MS, Hirata T, Romero MF, Dow JAT, Stoller ML. Drosophila melanogaster as an emerging translational model of human nephrolithiasis. J Urol 2013; 190:1648-56. [PMID: 23500641 PMCID: PMC3842186 DOI: 10.1016/j.juro.2013.03.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2013] [Indexed: 10/27/2022]
Abstract
PURPOSE The limitations imposed by human clinical studies and mammalian models of nephrolithiasis have hampered the development of effective medical treatments and preventive measures for decades. The simple but elegant Drosophila melanogaster is emerging as a powerful translational model of human disease, including nephrolithiasis. It may provide important information essential to our understanding of stone formation. We present the current state of research using D. melanogaster as a model of human nephrolithiasis. MATERIALS AND METHODS We comprehensively reviewed the English language literature using PubMed®. When necessary, authoritative texts on relevant subtopics were consulted. RESULTS The genetic composition, anatomical structure and physiological function of Drosophila malpighian tubules are remarkably similar to those of the human nephron. The direct effects of dietary manipulation, environmental alteration and genetic variation on stone formation can be observed and quantified in a matter of days. Several Drosophila models of human nephrolithiasis have been developed, including genetically linked and environmentally induced stones. A model of calcium oxalate stone formation is among the most recent fly models of human nephrolithiasis. CONCLUSIONS The ability to readily manipulate and quantify stone formation in D. melanogaster models of human nephrolithiasis presents the urological community with a unique opportunity to increase our understanding of this enigmatic disease.
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Affiliation(s)
- Joe Miller
- University of California-San Francisco, San Francisco, California.
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Worcester EM, Evan AP, Coe FL, Lingeman JE, Krambeck A, Sommers A, Phillips CL, Milliner D. A test of the hypothesis that oxalate secretion produces proximal tubule crystallization in primary hyperoxaluria type I. Am J Physiol Renal Physiol 2013; 305:F1574-84. [PMID: 24089413 DOI: 10.1152/ajprenal.00382.2013] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The sequence of events by which primary hyperoxaluria type 1 (PH1) causes renal failure is unclear. We hypothesize that proximal tubule (PT) is vulnerable because oxalate secretion raises calcium oxalate (CaOx) supersaturation (SS) there, leading to crystal formation and cellular injury. We studied cortical and papillary biopsies from two PH1 patients with preserved renal function, and seven native kidneys removed from four patients at the time of transplant, after short-term (2) or longer term (2) dialysis. In these patients, and another five PH1 patients without renal failure, we calculated oxalate secretion, and estimated PT CaOx SS. Plasma oxalate was elevated in all PH1 patients and inverse to creatinine clearance. Renal secretion of oxalate was present in all PH1 but rare in controls. PT CaOx SS was >1 in all nonpyridoxine-responsive PH1 before transplant and most marked in patients who developed end stage renal disease (ESRD). PT from PH1 with preserved renal function had birefringent crystals, confirming the presence of CaOx SS, but had no evidence of cortical inflammation or scarring by histopathology or hyaluronan staining. PH1 with short ESRD showed CaOx deposition and hyaluronan staining particularly at the corticomedullary junction in distal PT while cortical collecting ducts were spared. Longer ESRD showed widespread cortical CaOx, and in both groups papillary tissue had marked intratubular CaOx deposits and fibrosis. CaOx SS in PT causes CaOx crystal formation, and CaOx deposition in distal PT appears to be associated with ESRD. Minimizing PT CaOx SS may be important for preserving renal function in PH1.
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Affiliation(s)
- Elaine M Worcester
- Nephrology Section, MC5100, Univ. of Chicago, School of Medicine, 5841 South Maryland Ave., Chicago, IL 60637.
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27
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Soleimani M. SLC26 Cl-/HCO3- exchangers in the kidney: roles in health and disease. Kidney Int 2013; 84:657-66. [PMID: 23636174 PMCID: PMC10947778 DOI: 10.1038/ki.2013.138] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/25/2013] [Accepted: 02/14/2013] [Indexed: 12/30/2022]
Abstract
Solute-linked carrier 26 (SLC26) isoforms constitute a conserved family of anion transporters with 10 distinct members. Except for SLC26A5 (prestin), all can operate as multifunctional anion exchangers, with three members (SLC26A7, SLC26A9, and SLC26A11) also capable of functioning as chloride channels. Several SLC26 isoforms can specifically mediate Cl(-)/HCO(3)(-) exchange. These include SLC26A3, A4, A6, A7, A9, and A11, which are expressed in the kidney except for SLC26A3 (DRA), which is predominantly expressed in the intestine. SLC26 Cl(-)/HCO(3)(-) exchanger isoforms display unique nephron segment distribution patterns with distinct subcellular localization in the kidney tubules. Together with studies in pathophysiologic states and the examination of genetically engineered mouse models, the evolving picture points to important roles for the SLC26 family in health and disease states. This review summarizes recent advances in the characterization of the SLC26 Cl(-)/HCO(3)(-) exchangers in the kidney with emphasis on their essential role in diverse physiological processes, including chloride homeostasis, oxalate excretion and kidney stone formation, vascular volume and blood pressure regulation, and acid-base balance.
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Affiliation(s)
- Manoocher Soleimani
- 1] Center on Genetics of Transport and Epithelial Biology, University of Cincinnati, Cincinnati, Ohio, USA [2] Research Services, Veterans Affairs Medical Center, Cincinnati, Ohio, USA [3] Department of Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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Identification of SLC26A transporters involved in the Cl⁻/HCO₃⁻ exchange in proximal tubular cells from WKY and SHR. Life Sci 2013; 93:435-40. [PMID: 23933130 DOI: 10.1016/j.lfs.2013.07.026] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 07/16/2013] [Accepted: 07/29/2013] [Indexed: 12/11/2022]
Abstract
AIMS slc26a proteins are responsible for a large number of functions either in normal physiology or in human disease. We have previously reported that proximal tubular epithelial (PTE) cells immortalized from spontaneously hypertensive rats (SHRs) were endowed with increased Cl(-)/HCO3(-) exchanger activity and slc26a6 protein expression compared with PTE cells immortalized from normotensive Wistar Kyoto (WKY) rats. The aim of the present study was to identify slc26a members responsible for the Cl(-)/HCO3(-) exchange in WKY and SHR PTE cells. MAIN METHODS Cl(-)/HCO3(-) exchanger activity was assessed as the initial rate of pHi recovery after removal of HCO3(-) or after removal of Cl(-). The presence of slc26a genes was evaluated by means of reverse transcriptase-PCR (RT-PCR) in WKY and SHR PTE cell lines and in the kidney of WKY and SHR. Transcript abundance was measured by quantitative real-time polymerase chain reaction (PCR). KEY FINDINGS We detected slc26a4, slc26a6, slc26a7 and slc26a9 transcripts in the rat kidney of WKY and SHR. In WKY and SHR PTE cell lines we detected slc26a4, slc26a6 and slc26a9 transcripts, which were, respectively, 12-, 4- and 15-fold upregulated in SHR cells. Gene silencing with small interfering RNAs (siRNAs) targeting slc26a4, slc26a6 and slc26a9 reduced Cl(-)/HCO3(-) exchanger activity in both cell lines. SIGNIFICANCE These results indicate that Cl(-)/HCO3(-) exchanger activity is mediated by, at least in part, slc26a4, slc26a6 and slc26a9 in cultured WKY and SHR cells. The overexpression of these slc26a members in SHR cells may correspond to an adaptive process to cope with the sustained increase in proximal tubular sodium reabsorption.
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29
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Abstract
The kidney plays a fundamental role in maintaining body salt and fluid balance and blood pressure homeostasis through the actions of its proximal and distal tubular segments of nephrons. However, proximal tubules are well recognized to exert a more prominent role than distal counterparts. Proximal tubules are responsible for reabsorbing approximately 65% of filtered load and most, if not all, of filtered amino acids, glucose, solutes, and low molecular weight proteins. Proximal tubules also play a key role in regulating acid-base balance by reabsorbing approximately 80% of filtered bicarbonate. The purpose of this review article is to provide a comprehensive overview of new insights and perspectives into current understanding of proximal tubules of nephrons, with an emphasis on the ultrastructure, molecular biology, cellular and integrative physiology, and the underlying signaling transduction mechanisms. The review is divided into three closely related sections. The first section focuses on the classification of nephrons and recent perspectives on the potential role of nephron numbers in human health and diseases. The second section reviews recent research on the structural and biochemical basis of proximal tubular function. The final section provides a comprehensive overview of new insights and perspectives in the physiological regulation of proximal tubular transport by vasoactive hormones. In the latter section, attention is particularly paid to new insights and perspectives learnt from recent cloning of transporters, development of transgenic animals with knockout or knockin of a particular gene of interest, and mapping of signaling pathways using microarrays and/or physiological proteomic approaches.
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Affiliation(s)
- Jia L Zhuo
- Laboratory of Receptor and Signal Transduction, Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi, USA.
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30
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Parker MD, Boron WF. The divergence, actions, roles, and relatives of sodium-coupled bicarbonate transporters. Physiol Rev 2013; 93:803-959. [PMID: 23589833 PMCID: PMC3768104 DOI: 10.1152/physrev.00023.2012] [Citation(s) in RCA: 208] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The mammalian Slc4 (Solute carrier 4) family of transporters is a functionally diverse group of 10 multi-spanning membrane proteins that includes three Cl-HCO3 exchangers (AE1-3), five Na(+)-coupled HCO3(-) transporters (NCBTs), and two other unusual members (AE4, BTR1). In this review, we mainly focus on the five mammalian NCBTs-NBCe1, NBCe2, NBCn1, NDCBE, and NBCn2. Each plays a specialized role in maintaining intracellular pH and, by contributing to the movement of HCO3(-) across epithelia, in maintaining whole-body pH and otherwise contributing to epithelial transport. Disruptions involving NCBT genes are linked to blindness, deafness, proximal renal tubular acidosis, mental retardation, and epilepsy. We also review AE1-3, AE4, and BTR1, addressing their relevance to the study of NCBTs. This review draws together recent advances in our understanding of the phylogenetic origins and physiological relevance of NCBTs and their progenitors. Underlying these advances is progress in such diverse disciplines as physiology, molecular biology, genetics, immunocytochemistry, proteomics, and structural biology. This review highlights the key similarities and differences between individual NCBTs and the genes that encode them and also clarifies the sometimes confusing NCBT nomenclature.
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Affiliation(s)
- Mark D Parker
- Dept. of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106-4970, USA.
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31
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Chen AP, Chang MH, Romero MF. Functional analysis of nonsynonymous single nucleotide polymorphisms in human SLC26A9. Hum Mutat 2012; 33:1275-84. [PMID: 22544634 PMCID: PMC3399991 DOI: 10.1002/humu.22107] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Accepted: 04/16/2012] [Indexed: 01/13/2023]
Abstract
Slc26 anion transporters play crucial roles in transepithelial Cl(-) absorption and HCO(3)(-) secretion; Slc26 protein mutations lead to several diseases. Slc26a9 functions as a Cl(-) channel and electrogenic Cl(-)--HCO(3)(-) exchanger, and can interact with cystic fibrosis transmembrane conductance regulator. Slc26a9(-/-) mice have reduced gastric acid secretion, yet no human disease is currently associated with SLC26A9 coding mutations. Therefore, we tested the function of nonsynonymous, coding, single nucleotide polymorphisms (cSNPs) of SLC26A9. Presently, eight cSNPs are NCBI documented: Y70N, T127N, I384T, R575W, P606L, V622L, V744M, and H748R. Using two-electrode voltage-clamp and anion selective electrodes, we measured the biophysical consequences of these cSNPs. Y70N (cytoplasmic N-terminus) displays higher channel activity and enhanced Cl(-)--HCO(3)(-) exchange. T127N (transmembrane) results in smaller halide currents but not for SCN(-). V622L (STAS domain) and V744M (STAS adjacent) decreased plasma membrane expression, which partially accounts for decreased whole cell currents. Nevertheless, V622L transport is reduced to ∼50%. SLC26A9 polymorphisms lead to several function modifications (increased activity, decreased activity, altered protein expression), which could lead to a spectrum of pathophysiologies. Thus, knowing an individual's SLC26A9 genetics becomes important for understanding disease potentially caused by SLC26A9 mutations or modifying diseases, for example, cystic fibrosis. Our results also provide a framework to understand SLC26A9 transport modalities and structure-function relationships.
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Affiliation(s)
- An-Ping Chen
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Min-Hwang Chang
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Michael F. Romero
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
- Nephrology & Hypertension, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
- O’Brien Urology Research Center, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
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32
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Markovich D. Slc13a1 and Slc26a1 KO models reveal physiological roles of anion transporters. Physiology (Bethesda) 2012; 27:7-14. [PMID: 22311966 DOI: 10.1152/physiol.00041.2011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Anion transporters NaS1 (SLC13A1) and Sat1 (SLC26A1) mediate sulfate (re)absorption across renal proximal tubule and small intestinal epithelia, thereby regulating blood sulfate levels. Disruption of murine NaS1 and Sat1 genes leads to hyposulfatemia and hypersulfaturia. Sat1-null mice also exhibit hyperoxalemia, hyperoxaluria, and calcium oxalate urolithiasis. This review will highlight the current pathophysiological features of NaS1- and Sat1-null mice resulting from alterations in circulating sulfate and oxalate anion levels.
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Affiliation(s)
- Daniel Markovich
- Molecular Physiology Group, School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
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33
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Liu Y, Wang DK, Chen LM. The physiology of bicarbonate transporters in mammalian reproduction. Biol Reprod 2012; 86:99. [PMID: 22262691 DOI: 10.1095/biolreprod.111.096826] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
HCO(3)(-) plays critically important roles during virtually the entire process of reproduction in mammals, including spermatogenesis, sperm capacitation, fertilization, and development of early stage embryos. Therefore, the acid-base balance in the male and female reproductive tracts must be finely modulated. The fluid milieu in the epididymis is acidic, containing very low concentration of HCO(3)(-). In this acidic low HCO(3)(-) environment, mature sperm are rendered quiescent in the epididymis. In contrast, the luminal fluid in the female uterus and oviduct is alkaline, with very high concentration of HCO(3)(-) that is essential for sperm to fulfill fertilization. HCO(3)(-) transporter of solute carrier 4 (SLC4) and SLC26 families represent the major carriers for HCO(3)(-) transport across the plasma membrane. These transporters play critical roles in intracellular pH regulation and transepithelial HCO(3)(-) transport. The physiological roles of these transporters in mammalian reproduction are of fundamental interest to investigators. Here we review recent progress in understanding the expression of HCO(3)(-) transporters in reproductive tract tissues as well as the physiological roles of these transporters in mammalian reproduction.
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Affiliation(s)
- Ying Liu
- Department of Biological Sciences, Key Laboratory of Molecular Biophysics of Ministry of Education, Huazhong University of Science and Technology School of Life Science and Technology, Wuhan, China
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Hirata T, Czapar A, Brin LR, Haritonova A, Bondeson DP, Linser PJ, Cabrero P, Dow JAT, Romero MF. Ion and solute transport by Prestin in Drosophila and Anopheles. JOURNAL OF INSECT PHYSIOLOGY 2012; 58:563-569. [PMID: 22321763 PMCID: PMC3482613 DOI: 10.1016/j.jinsphys.2012.01.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Revised: 01/11/2012] [Accepted: 01/14/2012] [Indexed: 05/31/2023]
Abstract
The gut and Malpighian tubules of insects are the primary sites of active solute and water transport for controlling hemolymph and urine composition, pH, and osmolarity. These processes depend on ATPase (pumps), channels and solute carriers (Slc proteins). Maturation of genomic databases enables us to identify the putative molecular players for these processes. Anion transporters of the Slc4 family, AE1 and NDAE1, have been reported as HCO(3)(-) transporters, but are only part of the story. Here we report Dipteran (Drosophila melanogaster (d) and Anopheles gambiae (Ag)) anion exchangers, belonging to the Slc26 family, which are multi-functional anion exchangers. One Drosophila and two Ag homologues of mammalian Slc26a5 (Prestin) and Slc26a6 (aka, PAT1, CFEX) were identified and designated dPrestin, AgPrestinA and AgPrestinB. dPrestin and AgPrestinB show electrogenic anion exchange (Cl(-)/nHCO(3)(-), Cl(-)/SO(4)(2-) and Cl(-)/oxalate(2-)) in an oocyte expression system. Since these transporters are the only Dipteran Slc26 proteins whose transport is similar to mammalian Slc26a6, we submit that Dipteran Prestin are functional and even molecular orthologues of mammalian Slc26a6. OSR1 kinase increases dPrestin ion transport, implying another set of physiological processes controlled by WNK/SPAK signaling in epithelia. All of these mRNAs are highly expressed in the gut and Malpighian tubules. Dipteran Prestin proteins appear suited for central roles in bicarbonate, sulfate and oxalate metabolism including generating the high pH conditions measured in the Dipteran midgut lumen. Finally, we present and discuss Drosophila genetic models that integrate these processes.
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Affiliation(s)
- Taku Hirata
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
- Mayo Clinic O’Brien Urology Research Center, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Anna Czapar
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Lauren R. Brin
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
- Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Alyona Haritonova
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Daniel P. Bondeson
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
- Biochemistry & Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
- Mayo Clinic O’Brien Urology Research Center, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
| | - Paul J. Linser
- University of Florida Whitney Laboratory, 9505 Ocean Shore Blvd., St. Augustine FL, 32086
| | - Pablo Cabrero
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Julian A. T. Dow
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, KSA
| | - Michael F. Romero
- Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
- Mayo Clinic O’Brien Urology Research Center, Mayo Clinic College of Medicine, Rochester, MN 55905 USA
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Liu Z, Li GH, Huang JF, Murphy RW, Shi P. Hearing aid for vertebrates via multiple episodic adaptive events on prestin genes. Mol Biol Evol 2012; 29:2187-98. [PMID: 22416033 DOI: 10.1093/molbev/mss087] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Auditory detection is essential for survival and reproduction of vertebrates, yet the genetic changes underlying the evolution and diversity of hearing are poorly documented. Recent discoveries concerning prestin, which is responsible for cochlear amplification by electromotility, provide an opportunity to redress this situation. We identify prestin genes from the genomes of 14 vertebrates, including three fishes, one amphibian, one lizard, one bird, and eight mammals. An evolutionary analysis of these sequences and 34 previously known prestin genes reveals for the first time that this hearing gene was under positive selection in the most recent common ancestor (MRCA) of tetrapods. This discovery might document the genetic basis of enhanced high sound sensibility in tetrapods. An investigation of the adaptive gain and evolution of electromotility, an important evolutionary innovation for the highest hearing ability of mammals, detects evidence for positive selections on the MRCA of mammals, therians, and placentals, respectively. It is suggested that electromotility determined by prestin might initially appear in the MRCA of mammals, and its functional improvements might occur in the MRCA of therian and placental mammals. Our patch clamp experiments further support this hypothesis, revealing the functional divergence of voltage-dependent nonlinear capacitance of prestin from platypus, opossum, and gerbil. Moreover, structure-based cdocking analyses detect positively selected amino acids in the MRCA of placental mammals that are key residues in sulfate anion transport. This study provides new insights into the adaptation and functional diversity of hearing sensitivity in vertebrates by evolutionary and functional analysis of the hearing gene prestin.
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Affiliation(s)
- Zhen Liu
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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Abstract
SLC4A gene family proteins include bicarbonate transporters that move HCO(3)(-) across the plasma membrane and regulate intracellular pH and transepithelial movement of acid-base equivalents. These transporters are Cl/HCO(3) exchangers, electrogenic Na/HCO(3) cotransporters, electroneutral Na/HCO(3) cotransporters, and Na(+)-driven Cl/HCO(3) exchanger. Studies of the bicarbonate transporters in vitro and in vivo have demonstrated their physiological importance for acid-base homeostasis at the cellular and systemic levels. Recent advances in structure/function analysis have also provided valuable information on domains or motifs critical for regulation, ion translocation, and protein topology. This chapter focuses on the molecular mechanisms of ion transport along with associated structural aspects from mutagenesis of particular residues and from chimeric constructs. Structure/function studies have helped to understand the mechanism by which ion substrates are moved via the transporters. This chapter also describes some insights into the structure of SLC4A1 (AE1) and SLC4A4 (NBCe1) transporters. Finally, as some SLC4A transporters exist in concert with other proteins in the cells, the structural features associated with protein-protein interactions are briefly discussed.
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Affiliation(s)
- Inyeong Choi
- Department of Physiology, Emory University, Atlanta, Georgia, USA.
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Abstract
Hyperoxaluria leads to urinary calcium oxalate (CaOx) supersaturation, resulting in the formation and retention of CaOx crystals in renal tissue. CaOx crystals may contribute to the formation of diffuse renal calcifications (nephrocalcinosis) or stones (nephrolithiasis). When the innate renal defense mechanisms are suppressed, injury and progressive inflammation caused by these CaOx crystals, together with secondary complications such as tubular obstruction, may lead to decreased renal function and in severe cases to end-stage renal failure. For decades, research on nephrocalcinosis and nephrolithiasis mainly focused on both the physicochemistry of crystal formation and the cell biology of crystal retention. Although both have been characterized quite well, the mechanisms involved in establishing urinary supersaturation in vivo are insufficiently understood, particularly with respect to oxalate. Therefore, current therapeutic strategies often fail in their compliance or effectiveness, and CaOx stone recurrence is still common. As the etiology of hyperoxaluria is diverse, a good understanding of how oxalate is absorbed and transported throughout the body, together with a better insight in the regulatory mechanisms, is crucial in the setting of future treatment strategies of this disorder. In this review, the currently known mechanisms of oxalate handling in relevant organs will be discussed in relation to the different etiologies of hyperoxaluria. Furthermore, future directions in the treatment of hyperoxaluria will be covered.
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Abstract
The electroneutral Na(+)-HCO(3)(-) cotransporter NBCn1 (SLC4A7) contributes to intracellular pH maintenance and transepithelial HCO(3)(-) movement. In this study, we expressed NBCn1 in Xenopus oocytes and examined the effect of NBCn1 on oocyte NH(4)(+) transport by analysing changes in membrane potential, current and intracellular pH mediated by NH(4)Cl. In the presence of HCO(3)(-)/CO(2), applying NH(4)Cl (20 mm) produced intracellular acidification of oocytes. The acidification was faster in oocytes expressing NBCn1 than in control oocytes injected with water; however, NH(4)Cl-mediated membrane depolarization was smaller in oocytes expressing NBCn1. In HCO(3)(-)/CO(2)-free solution, NH(4)Cl produced a smaller inward current in NBCn1-expressing oocytes (56% inhibition by 20 mm NH(4)Cl, measured at --60 mV), while minimally affecting intracellular acidification. The inhibition of the current by NBCn1 was unaffected when BaCl(2) replaced KCl. Current-voltage relationships showed a positive and nearly linear relationship between NH(4)Cl-mediated current and voltage, which was markedly reduced by NBCn1. Large basal currents (before NH(4)Cl exposure) were produced in NBCn1-expressing oocytes owing to the previously characterized channel-like activity of NBCn1. Inhibiting this channel-like activity by Na(+) removal abolished the inhibitory effect of NBCn1 on NH(4)Cl-mediated currents. The currents were progressively reduced over 72-120 h after NBCn1 cRNA injection, during which the channel-like activity was high. These results indicate that NBCn1 stimulates NH(4)(+) transport by its Na(+)-HCO(3)(-) cotransport activity, while reducing NH(4)(+) conductance by its channel-like activity.
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Affiliation(s)
- Soojung Lee
- Department of Physiology, Emory University School of Medicine, Atlanta, GA 30322, USA
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Intestinal transport following transfer to increased salinity in an anadromous fish (Oncorhynchus mykiss). Comp Biochem Physiol A Mol Integr Physiol 2011; 159:150-8. [DOI: 10.1016/j.cbpa.2011.02.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 02/12/2011] [Accepted: 02/14/2011] [Indexed: 11/23/2022]
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Markovich D. Physiological roles of renal anion transporters NaS1 and Sat1. Am J Physiol Renal Physiol 2011; 300:F1267-70. [PMID: 21490138 DOI: 10.1152/ajprenal.00061.2011] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
This review will briefly summarize current knowledge on the renal anion transporters sodium-sulfate cotransporter-1 (NaS1; Slc13a1) and sulfate-anion transporter-1 (Sat1; Slc26a1). NaS1 and Sat1 mediate renal proximal tubular sulfate reabsorption and thereby regulate blood sulfate levels. Sat1 also mediates renal oxalate transport and controls blood oxalate levels. Targeted disruption of murine NaS1 and Sat1 leads to hyposulfatemia and hypersulfaturia. Sat1 null mice also exhibit hyperoxalemia, hyperoxaluria, and calcium oxalate urolithiasis. NaS1 and Sat1 null mice also have other phenotypes that result due to changes in blood sulfate and oxalate levels. Experimental data indicate that NaS1 is essential for maintaining sulfate homeostasis, whereas Sat1 controls both sulfate and oxalate homeostasis in vivo.
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Affiliation(s)
- Daniel Markovich
- Molecular Physiology Group, School of Biomedical Sciences, Univ. of Queensland, St. Lucia, Australia.
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Almomani EY, Chu CYS, Cordat E. Mis-trafficking of bicarbonate transporters: implications to human diseases. Biochem Cell Biol 2011; 89:157-77. [PMID: 21455268 DOI: 10.1139/o10-153] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2025] Open
Abstract
Bicarbonate is a waste product of mitochondrial respiration and one of the main buffers in the human body. Thus, bicarbonate transporters play an essential role in maintaining acid-base balance but also during fetal development as they ensure tight regulation of cytosolic and extracellular environments. Bicarbonate transporters belong to two gene families, SLC4A and SLC26A. Proteins from these two families are widely expressed, and thus mutations in their genes result in various diseases that affect bones, pancreas, reproduction, brain, kidneys, eyes, heart, thyroid, red blood cells, and lungs. In this minireview, we discuss the current state of knowledge regarding the effect of SLC4A and SLC26A mutants, with a special emphasis on mutants that have been studied in mammalian cell lines and how they correlate with phenotypes observed in mice models.
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Affiliation(s)
- Ensaf Y Almomani
- Membrane Protein Research Group, Department of Physiology, School of Molecular and Systems Medicine, University of Alberta, Edmonton, AB, Canada
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Abstract
WNKs are serine/threonine kinases that comprise a unique branch of the kinome. They are so-named owing to the unusual placement of an essential catalytic lysine. WNKs have now been identified in diverse organisms. In humans and other mammals, four genes encode WNKs. WNKs are widely expressed at the message level, although data on protein expression is more limited. Soon after the WNKs were identified, mutations in genes encoding WNK1 and -4 were determined to cause the human disease familial hyperkalemic hypertension (also known as pseudohypoaldosteronism II, or Gordon's Syndrome). For this reason, a major focus of investigation has been to dissect the role of WNK kinases in renal regulation of ion transport. More recently, a different mutation in WNK1 was identified as the cause of hereditary sensory and autonomic neuropathy type II, an early-onset autosomal disease of peripheral sensory nerves. Thus the WNKs represent an important family of potential targets for the treatment of human disease, and further elucidation of their physiological actions outside of the kidney and brain is necessary. In this review, we describe the gene structure and mechanisms regulating expression and activity of the WNKs. Subsequently, we outline substrates and targets of WNKs as well as effects of WNKs on cellular physiology, both in the kidney and elsewhere. Next, consequences of these effects on integrated physiological function are outlined. Finally, we discuss the known and putative pathophysiological relevance of the WNKs.
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Affiliation(s)
- James A McCormick
- Division of Nephrology and Hypertension, Oregon Health and Science University and Veterans Affairs Medical Center, Portland, Oregon 97239, USA.
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Oehlschläger S, Fuessel S, Meye A, Herrmann J, Lotzkat U, Froehner M, Albrecht S, Wirth MP. Importance of erythrocyte band III anion transporter (SLC4A1) on oxalate clearance of calcium oxalate monohydrate stone-formering patients vs. normal controls. Urology 2010; 77:250.e1-5. [PMID: 20947140 DOI: 10.1016/j.urology.2010.06.043] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2009] [Revised: 05/30/2010] [Accepted: 06/22/2010] [Indexed: 10/19/2022]
Abstract
OBJECTIVES To examine erythrocyte band III transport protein (SLC4A1), erythrocyte oxalate flux, and plasmatic, cellular, and urine oxalate concentrations and blood gas analyses in calcium oxalate monohydrate stone-forming patients (COM) in comparison with normal controls (NC). METHODS Isolated red cells from 51 NC and 25 COM cases were divided for cellular oxalate measurement and for measurement of transcellular erythrocyte oxalate flux (pH 7.48-8.24). SLC4A1 protein levels were determined by Western blot analyses. Plasmatic and urinary oxalate levels and the venous blood gas analysis were measured simultaneously. RESULTS SLC4A1 protein levels were significantly higher in COM (8.76 ± 2.12) than in NC (4.17 ± 0.61; P < .02). Cellular oxalate and venous HCO(3)(-) were significantly lower in COM (2.35 ± 0.26 μmol/L) and (24.06 ± 0.24 mmo/l) than in NC (4.03 ± 0.49 μmol/L; P < .05) and (24.93 ± 0.17 mmol/L; P < .01). Urinary oxalate was significantly higher in COM (0.31 ± 0.02 mmol/L) than in NC (0.25 ± 0.01 mmol/L; P < .04). The erythrocyte transmembrane oxalate flux correlated with the pH value and with the urinary oxalate in both groups (r = .25-.55; P = .01). With increased pH values, the oxalate flux showed inverse effects in both groups. CONCLUSIONS SLC4A1 associated changes of HCO(3)(-) and pH levels influenced the cellular oxalate levels and urinary oxalate clearance. Under normal conditions (pH 7.55) the oxalate efflux in COM was comparable with the acid stimulated oxalate efflux in NC. The addition of HCO(3)(-) compensated the flux of COM stone formers to the levels of normal controls.
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Bench-to-bedside review: Chloride in critical illness. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2010; 14:226. [PMID: 20663180 PMCID: PMC2945073 DOI: 10.1186/cc9052] [Citation(s) in RCA: 217] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Chloride is the principal anion in the extracellular fluid and is the second main contributor to plasma tonicity. Its concentration is frequently abnormal in intensive care unit patients, often as a consequence of fluid therapy. Yet chloride has received less attention than any other ion in the critical care literature. New insights into its physiological roles have emerged together with progress in understanding the structures and functions of chloride channels. In clinical practice, interest in a physicochemical approach to acid-base physiology has directed renewed attention to chloride as a major determinant of acid-base status. It has also indirectly helped to generate interest in other possible effects of disorders of chloraemia. The present review summarizes key aspects of chloride physiology, including its channels, as well as the clinical relevance of disorders of chloraemia. The paper also highlights current knowledge on the impact of different types of intravenous fluids on chloride concentration and the potential effects of such changes on organ physiology. Finally, the review examines the potential intensive care unit practice implications of a better understanding of chloride.
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45
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Pasqualetto E, Aiello R, Gesiot L, Bonetto G, Bellanda M, Battistutta R. Structure of the cytosolic portion of the motor protein prestin and functional role of the STAS domain in SLC26/SulP anion transporters. J Mol Biol 2010; 400:448-62. [PMID: 20471983 DOI: 10.1016/j.jmb.2010.05.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2010] [Revised: 05/04/2010] [Accepted: 05/07/2010] [Indexed: 12/22/2022]
Abstract
Prestin is the motor protein responsible for the somatic electromotility of cochlear outer hair cells and is essential for normal hearing sensitivity and frequency selectivity of mammals. Prestin is a member of mammalian solute-linked carrier 26 (SLC26) anion exchangers, a family of membrane proteins capable of transporting a wide variety of monovalent and divalent anions. SLC26 transporters play important roles in normal human physiology in different tissues, and many of them are involved in genetic diseases. SLC26 and related SulP transporters carry a hydrophobic membrane core and a C-terminal cytosolic portion that is essential in plasma membrane targeting and protein function. This C-terminal portion is mainly composed of a STAS (sulfate transporters and anti-sigma factor antagonist) domain, whose name is due to a remote but significant sequence similarity with bacterial ASA (anti-sigma factor antagonist) proteins. Here we present the crystal structure at 1.57 A resolution of the cytosolic portion of prestin, the first structure of a SulP transporter STAS domain, and its characterization in solution by heteronuclear multidimensional NMR spectroscopy. Prestin STAS significantly deviates from the related bacterial ASA proteins, especially in the N-terminal region, which-although previously considered merely as a generic linker between the domain and the last transmembrane helix-is indeed fully part of the domain. Hence, unexpectedly, our data reveal that the STAS domain starts immediately after the last transmembrane segment and lies beneath the lipid bilayer. A structure-function analysis suggests that this model can be a general template for most SLC26 and SulP anion transporters and supports the notion that STAS domains are involved in functionally important intramolecular and intermolecular interactions. Mapping of disease-associated or functionally harmful mutations on STAS structure indicates that they can be divided into two categories: those causing significant misfolding of the domain and those altering its interaction properties.
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Affiliation(s)
- Elisa Pasqualetto
- Department of Chemical Sciences, University of Padua, via Marzolo 1, 35131 Padua, Italy
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46
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Bayaa M, Vulesevic B, Esbaugh A, Braun M, Ekker ME, Grosell M, Perry SF. The involvement of SLC26 anion transporters in chloride uptake in zebrafish (Danio rerio) larvae. ACTA ACUST UNITED AC 2009; 212:3283-95. [PMID: 19801433 DOI: 10.1242/jeb.033910] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
After demonstrating phylogenetic relatedness to orthologous mammalian genes, tools were developed to investigate the roles of three members (A3, A4 and A6c) of the SLC26 anion exchange gene family in Cl- uptake and HCO3 excretion in embryos and larvae of zebrafish (Danio rerio). Whole-mount in situ hybridization revealed the presence of SLC26 mRNA in gill primordia, mesonephros and heart (slc26a3 and a4 only) at 5-9 days postfertilization (d.p.f.). SLC26A3 protein was highly expressed in lateral line neuromasts and within the gill, was localized to a sub-population of epithelial cells, which often (but not always) coexpressed Na+/K+-ATPase. SLC26 mRNA levels increased with developmental age, peaking at 5-10 d.p.f.; the largest increases in rates of Cl- uptake (JinCl-) preceded the mRNA spike, occurring at 2-5 d.p.f. Raising zebrafish in water with a low [Cl-] caused marked increases in JinCl- at 3-10 d.p.f. and was associated with increased levels of SLC26 mRNA. Raising fish in water of high [Cl-] was without effect on JinCl- or SLC26 transcript abundance. Selective gene knockdown using morpholino antisense oligonucleotides demonstrated a significant role for SLC26A3 in Cl- uptake in larval fish raised in control water and roles for A3, A4 and A6c in fish raised in water with low [Cl-]. Prolonged (7 days) or acute (24 h) exposure of fish to elevated (2 or 5 mmol l(-1)) ambient [HCO3-] caused marked increases in Cl- uptake when determined in water of normal [HCO3-] that were accompanied by elevated levels of SLC26 mRNA. The increases in JinCl- associated with high ambient [HCO3-] were not observed in the SLC26 morphants (significant only at 5 mmol l(-1) HCO3- for A4 and 2 mmol l(-1) HCO3- for A6c). Net base excretion was markedly inhibited in the slc26a3 and a6c morphants thereby implicating these genes in Cl-/HCO3- exchange. The results suggest that under normal conditions, Cl- uptake in zebrafish larvae is mediated by SLC26A3 Cl-/HCO3- exchangers but under conditions necessitating higher rates of high affinity Cl- uptake, SlC26A4 and SLC26A6c may assume a greater role.
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Affiliation(s)
- M Bayaa
- Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
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Wang X, Armando I, Upadhyay K, Pascua A, Jose PA. The regulation of proximal tubular salt transport in hypertension: an update. Curr Opin Nephrol Hypertens 2009; 18:412-420. [PMID: 19654544 PMCID: PMC3722593 DOI: 10.1097/mnh.0b013e32832f5775] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
PURPOSE OF REVIEW Renal proximal tubular sodium reabsorption is regulated by sodium transporters, including the sodium glucose transporter, sodium amino acid transporter, sodium hydrogen exchanger isoform 3 and sodium phosphate cotransporter type 2 located at the luminal/apical membrane, and sodium bicarbonate cotransporter and Na+/K+ATPase located at the basolateral membrane. This review summarizes recent studies on sodium transporters that play a major role in the increase in blood pressure in essential/polygenic hypertension. RECENT FINDINGS Sodium transporters and Na+/K+ATPase are segregated in membrane lipid and nonlipid raft microdomains that regulate their activities and trafficking via cytoskeletal proteins. The increase in renal proximal tubule ion transport in polygenic hypertension is primarily due to increased activity of NHE3 and Cl/HCO3 exchanger at the luminal/apical membrane and a primary or secondary increase in Na+/K+ATPase activity. SUMMARY The increase in renal proximal tubule ion transport in hypertension is due to increased actions by prohypertensive factors that are unopposed by antihypertensive factors.
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Affiliation(s)
- Xiaoyan Wang
- Center for Molecular Physiology Research, Children's Research Institute, Children's National Medical Center, Washington, District of Columbia, USA
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Perry SF, Vulesevic B, Grosell M, Bayaa M. Evidence that SLC26 anion transporters mediate branchial chloride uptake in adult zebrafish (Danio rerio). Am J Physiol Regul Integr Comp Physiol 2009; 297:R988-97. [PMID: 19641131 DOI: 10.1152/ajpregu.00327.2009] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Experiments were performed to test the hypothesis that three members of the SLC26 anion transporter gene family (SLC26a3, A4, and A6; hereafter termed za3, za4, and za6) mediate branchial Cl(-)/HCO(3)(-) exchange in adult zebrafish (Danio rerio). Real-time RT-PCR demonstrated that the gill expressed relatively high levels of za6 mRNA; za3 and za4 mRNA, while present, were less abundant. Also, za4 and za6 were expressed at relatively high levels in the kidney. The results of in situ hybridization or immunocytochemistry (za3 only) experiments performed on gill sections revealed that the SLC26 transporters were predominantly expressed on the filament epithelium (especially within the interlamellar regions) and to a lesser extent on the lamellar epithelium at the base of lamellae. This distribution pattern suggests that the SLC26 anion transporters are localized to mitochondrion-rich cells (ionocytes). Transferring fish to water containing low [Cl(-)] (0.02 mmol/l) resulted in significant increases in branchial SLC26 mRNA expression after 5-10 days of exposure relative to fish raised in normal water [Cl(-)] (0.4 mmol/l); transferring fish to Cl(-)-enriched water (2.0 mmol/l) was without effect on mRNA levels. Transferring fish to water containing elevated levels of NaHCO(3) (10-12.5 mmol/l) caused marked increases in branchial SLC26 mRNA expression between 3 and 10 days of transfer that was associated with a significant 40% increase in Cl(-) uptake (as measured upon return to normal water after 7 days). A decrease in whole body net acid excretion (equivalent to an increase in net base excretion) in fish previously maintained in high [NaHCO(3)] water, concurrent with increases in Cl(-) uptake and SLC26 mRNA levels, suggests a role for these anion transporters in Cl(-) uptake and acid-base regulation owing to their Cl(-)/HCO(3)(-) exchange activities.
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Affiliation(s)
- S F Perry
- 1Department of Biology and Centre for Advanced Research in Environmental Genomics, University of Ottawa, Ottawa, Ontario, Canada.
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50
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Krick W, Schnedler N, Burckhardt G, Burckhardt BC. Ability of sat-1 to transport sulfate, bicarbonate, or oxalate under physiological conditions. Am J Physiol Renal Physiol 2009; 297:F145-54. [DOI: 10.1152/ajprenal.90401.2008] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Tubular reabsorption of sulfate is achieved by the sodium-dependent sulfate transporter, NaSi-1, located at the apical membrane, and the sulfate-anion exchanger, sat-1, located at the basolateral membrane. To delineate the physiological role of rat sat-1, [35S]sulfate and [14C]oxalate uptake into sat-1-expressing oocytes was determined under various experimental conditions. Influx of [35S]sulfate was inhibited by bicarbonate, thiosulfate, sulfite, and oxalate, but not by sulfamate and sulfide, in a competitive manner with Ki values of 2.7 ± 1.3 mM, 101.7 ± 9.7 μM, 53.8 ± 10.9 μM, and 63.5 ± 38.7 μM, respectively. Vice versa, [14C]oxalate uptake was inhibited by sulfate with a Ki of 85.9 ± 9.5 μM. The competitive type of inhibition indicates that these compounds are most likely substrates of sat-1. Physiological plasma bicarbonate concentrations (25 mM) reduced sulfate and oxalate uptake by more than 75%. Simultaneous application of sulfate, bicarbonate, and oxalate abolished sulfate as well as oxalate uptake. These data and electrophysiological studies using a two-electrode voltage-clamp device provide evidence that sat-1 preferentially works as an electroneutral sulfate-bicarbonate or oxalate-bicarbonate exchanger. In kidney proximal tubule cells, sat-1 likely completes sulfate reabsorption from the ultrafiltrate across the basolateral membrane in exchange for bicarbonate. In hepatocytes, oxalate extrusion is most probably mediated either by an exchange for sulfate or bicarbonate.
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