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Shmuel Muallem - One of the best experts on this subject based on the ideXlab platform.
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properties and function of the solute carrier 26 family of anion transporters
2016Co-Authors: Nikolay Shcheynikov, Ehud Ohana, Shmuel MuallemAbstract:The SLC26 family of anion transporters consists of 10 members that display remarkable functional and substrate diversity. Mutations in several members of the family have been identified as causing a variety of human diseases and mouse phenotype when deleted. The family drew the attention and strong interest of epithelial biologist with the identification of the first elusive luminal Cl−/HCO3− exchange, which turned to be the third member of the family SLC26A3. Fairly quick, progress since revealed that members of the family transport all halides, NO3−, SO42−, oxalate, and formate, among others. Members of the family can be grouped into three subgroups based on substrate selectivity and transport mode: the SO42− transporters SLC26A1 and SLC26A2; the anion exchangers 2Cl−/1HCO3− SLC26A3, 1Cl−/1HCO3− SLC26A4, and 1Cl−/2HCO3− SLC26A6; and the Cl− channels SLC26A7, SLC26A9, and SLC26A11. This chapter discusses structural features, transport properties, and regulation of the transporters that are essential to understand their functions and roles in human diseases.
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multiple roles of the so42 cl oh exchanger protein slc26a2 in chondrocyte functions
Journal of Biological Chemistry, 2014Co-Authors: Meeyoung Park, Ehud Ohana, Soo Young Choi, Myeongsok Lee, Jong Hoon Park, Shmuel MuallemAbstract:Mutations in the SO42−/Cl−/OH− exchanger Slc26a2 cause the disease diastrophic dysplasia (DTD), resulting in aberrant bone development and, therefore, skeletal deformities. DTD is commonly attributed to a lack of chondrocyte SO42− uptake and proteoglycan sulfation. However, the skeletal phenotype of patients with DTD is typified by reduction in cartilage and osteoporosis of the long bones. Chondrocytes of patients with DTD are irregular in size and have a reduced capacity for proliferation and terminal differentiation. This raises the possibility of additional roles for Slc26a2 in chondrocyte function. Here, we examined the roles of Slc26a2 in chondrocyte biology using two distinct systems: mouse progenitor mesenchymal cells differentiated to chondrocytes and freshly isolated mouse articular chondrocytes differentiated into hypertrophic chondrocytes. Slc26a2 expression was manipulated acutely by delivery of Slc26a2 or shSlc26a2 with lentiviral vectors. We demonstrate that slc26a2 is essential for chondrocyte proliferation and differentiation and for proteoglycan synthesis. Slc26a2 also regulates the terminal stage of chondrocyte cell size expansion. These findings reveal multiple roles for Slc26a2 in chondrocyte biology and emphasize the importance of Slc26a2-mediated protein sulfation in cell signaling, which may account for the complex phenotype of DTD.
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solute carrier family 26 member a2 slc26a2 protein functions as an electroneutral so42 oh cl exchanger regulated by extracellular cl
Journal of Biological Chemistry, 2012Co-Authors: Ehud Ohana, Nikolay Shcheynikov, Meeyoung Park, Shmuel MuallemAbstract:Slc26a2 is a ubiquitously expressed SO42− transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO42− and the ion gradients that mediate SO42− uptake are poorly understood. We report here that Slc26a2 functions as an SO42−/2OH−, SO42−/2Cl−, and SO42−/OH−/Cl− exchanger, depending on the Cl− and OH− gradients. At inward Cl− and outward pH gradients (high Cl−o and low pHo) Slc26a2 functions primarily as an SO42−o/2OH−i exchanger. At low Cl−o and high pHo Slc26a2 functions increasingly as an SO42−o/2Cl−i exchanger. The reverse is observed for SO42−i/2OH−o and SO42−i/2Cl−o exchange. Slc26a2 also exchanges Cl− for I−, Br−, and NO3− and Cl−o competes with SO42− on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO42−i/2OH−o exchange. Slc26a2 can transport oxalate in exchange for OH− and/or Cl− with properties similar to SO42− transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence 367GFXXP371 between TMD7 and TMD8 close to the conserved Glu417 in the permeation pathway. Mutation of Glu417 eliminated transport by Slc26a2, whereas mutation of Phe368 increased the affinity for SO42−o 8-fold while reducing the affinity for Cl−o 2 fold, but without affecting regulation by Cl−o. These findings clarify the mechanism of net SO42− transport and describe a novel regulation of Slc26a2 by an extracellular anion binding site and should help in further understanding aberrant SLC26A2 function in diastrophic dysplasia.
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diverse transport modes by the solute carrier 26 family of anion transporters
The Journal of Physiology, 2009Co-Authors: Ehud Ohana, Nikolay Shcheynikov, Dongki Yang, Shmuel MuallemAbstract:The solute carrier 26 (SLC26) transporters are anion transporters with diverse substrate specificity. Several members are ubiquitous while others show limited tissue distribution. They are expressed in many epithelia and to the extent known, play a central role in anion secretion and absorption. Members of the family are primarily Cl- transporters, although some members transport mainly SO(4)2-, Cl-, HCO(3)- or I-. A defining feature of the family is their functional diversity. Slc26a1 and Slc26a2 function as specific SO(4)2- transporters while Slc26a4 functions as an electroneutral Cl-/I-/HCO(3)- exchanger. Slc26a3 and SLC26A6 function as coupled electrogenic Cl-/HCO(3)- exchangers or as bona fide anion channels. SLC26A7 and SLC26A9 function exclusively as Cl- channels. This short review discusses the functional diversity of the SLC26 transporters.
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the slc26a4 transporter functions as an electroneutral cl i hco3 exchanger role of slc26a4 and SLC26A6 in i and hco3 secretion and in regulation of cftr in the parotid duct
The Journal of Physiology, 2008Co-Authors: Nikolay Shcheynikov, Lawrence P. Karniski, Dongki Yang, Youxue Wang, Weizong Zeng, Insuk So, Shmuel MuallemAbstract:Transcellular Cl− and HCO3− transport is a vital function of secretory epithelia and exit across the luminal membrane is mediated by members of the SLC26 transporters in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) channel. Typically, secretory epithelia express several SLC26 transporters in the same tissue; however, how their specific function is determined in vivo is not known. In the present work we used the parotid gland duct which expressed Slc26a4 and SLC26A6 and the model systems of Slc26a4−/− and SLC26A6−/− mice to study the role and regulation of these SLC26 transporters. We examined the transport modes of SLC26A4 expressed in Xenopus oocytes and report that SLC26A4 functions as a coupled, electroneutral I−/Cl−, I−/HCO3− and Cl−/HCO3− exchanger with 1: 1 stoichiometry, with I− as the preferred anion. In the duct, Slc26a4 is expressed in the luminal membrane and mainly mediates I− secretion with minimal role in luminal HCO3− transport. By contrast, SLC26A6 mediates luminal Cl−/HCO3− exchange activity with minimal role in I− secretion. Furthermore, silencing of CFTR altered Cl−/HCO3− exchange by SLC26A6, but had no effect on I− secretion by Slc26a4. Accordingly, deletion of SLC26A6, but not deletion of Slc26a4, results in dysregulation of CFTR. These findings provide the first evidence for a selective role of the SLC26 transporters expressed in the same tissue in epithelial anion transport and suggest that transport specificity is achieved by both the properties of the transporters and the composition of the complexes they form.
Aminata Toure - One of the best experts on this subject based on the ideXlab platform.
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functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the slc26 family of anion transporters slc26a8 and slc26a9 physiological and pathophysiological relevance
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Elma El Khouri, Aminata ToureAbstract:The solute carrier 26 (SLC26) proteins are transmembrane proteins located at the plasma membrane of the cells and transporting a variety of monovalent and divalent anions, including chloride, bicarbonate, sulfate and oxalate. In humans, 11 members have been identified (SLC26A1 to SLC26A11) and although part of them display a very restricted tissue expression pattern, altogether they are widely expressed in the epithelial cells of the body where they contribute to the composition and the pH regulation of the secreted fluids. Importantly, mutations in SLC26A2, A3, A4, and A5 have been associated with distinct human genetic recessive disorders (i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues. During the last decade, physical and functional interactions of SLC26 members with the cystic fibrosis transmembrane conductance regulator (CFTR) have been highly documented, leading to the model of a crosstalk based on the binding of the SLC26 STAS domain to the CFTR regulatory domain. In this review, we will focus on the functional interaction of SLC26A8 and SLC26A9 with the CFTR channel. In particular we will highlight the newly published studies indicating that mutations in SLC26A8 and SLC26A9 proteins are associated with a deregulation of the CFTR anion transport activity in the pathophysiological context of the sperm and the pulmonary cells. These studies confirm the physiological relevance of SLC26 and CFTR cross-regulation, opening new gates for the treatment of cystic fibrosis.
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functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the slc26 family of anion transporters slc26a8 and slc26a9 physiological and pathophysiological relevance
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Elma El Khouri, Aminata ToureAbstract:Abstract The solute carrier 26 (SLC26) proteins are transmembrane proteins located at the plasma membrane of the cells and transporting a variety of monovalent and divalent anions, including chloride, bicarbonate, sulfate and oxalate. In humans, 11 members have been identified (SLC26A1 to SLC26A11) and although part of them display a very restricted tissue expression pattern, altogether they are widely expressed in the epithelial cells of the body where they contribute to the composition and the pH regulation of the secreted fluids. Importantly, mutations in SLC26A2 , A3 , A4 , and A5 have been associated with distinct human genetic recessive disorders ( i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues. During the last decade, physical and functional interactions of SLC26 members with the cystic fibrosis transmembrane conductance regulator (CFTR) have been highly documented, leading to the model of a crosstalk based on the binding of the SLC26 STAS domain to the CFTR regulatory domain. In this review, we will focus on the functional interaction of SLC26A8 and SLC26A9 with the CFTR channel. In particular we will highlight the newly published studies indicating that mutations in SLC26A8 and SLC26A9 proteins are associated with a deregulation of the CFTR anion transport activity in the pathophysiological context of the sperm and the pulmonary cells. These studies confirm the physiological relevance of SLC26 and CFTR cross-regulation, opening new gates for the treatment of cystic fibrosis. This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.
Nikolay Shcheynikov - One of the best experts on this subject based on the ideXlab platform.
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properties and function of the solute carrier 26 family of anion transporters
2016Co-Authors: Nikolay Shcheynikov, Ehud Ohana, Shmuel MuallemAbstract:The SLC26 family of anion transporters consists of 10 members that display remarkable functional and substrate diversity. Mutations in several members of the family have been identified as causing a variety of human diseases and mouse phenotype when deleted. The family drew the attention and strong interest of epithelial biologist with the identification of the first elusive luminal Cl−/HCO3− exchange, which turned to be the third member of the family SLC26A3. Fairly quick, progress since revealed that members of the family transport all halides, NO3−, SO42−, oxalate, and formate, among others. Members of the family can be grouped into three subgroups based on substrate selectivity and transport mode: the SO42− transporters SLC26A1 and SLC26A2; the anion exchangers 2Cl−/1HCO3− SLC26A3, 1Cl−/1HCO3− SLC26A4, and 1Cl−/2HCO3− SLC26A6; and the Cl− channels SLC26A7, SLC26A9, and SLC26A11. This chapter discusses structural features, transport properties, and regulation of the transporters that are essential to understand their functions and roles in human diseases.
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irbit mediates synergy between ca2 and camp signaling pathways during epithelial transport in mice
Gastroenterology, 2013Co-Authors: Seonghee Park, Nikolay Shcheynikov, Jeong Hee Hong, Changyu Zheng, Suk Hyo Suh, Katsuhiro Kawaai, Hideaki Ando, Akihiro Mizutani, Takaya Abe, Hiroshi KiyonariAbstract:Background & Aims The cyclic adenosine monophosphate (cAMP) and Ca 2+ signaling pathways synergize to regulate many physiological functions. However, little is known about the mechanisms by which these pathways interact. We investigated the synergy between these signaling pathways in mouse pancreatic and salivary gland ducts. Methods We created mice with disruptions in genes encoding the solute carrier family 26, member 6 (SLC26A6 −/− mice) and inositol 1,4,5-triphosphate (InsP 3 ) receptor-binding protein released with InsP 3 (Irbit −/− ) mice. We investigated fluid secretion by sealed pancreatic ducts and the function of SLC26A6 and the cystic fibrosis transmembrane conductance regulator (CFTR) in HeLa cells and in ducts isolated from mouse pancreatic and salivary glands. SLC26A6 activity was assayed by measuring intracellular pH, and CFTR activity was assayed by measuring Cl – current. Protein interactions were determined by immunoprecipitation analyses. Results Irbit mediated the synergistic activation of CFTR and SLC26A6 by Ca 2+ and cAMP. In resting cells, Irbit was sequestered by InsP 3 receptors (IP 3 Rs) in the endoplasmic reticulum. Stimulation of Gs-coupled receptors led to phosphorylation of IP 3 Rs, which increased their affinity for InsP 3 and reduced their affinity for Irbit. Subsequent weak stimulation of Gq-coupled receptors, which led to production of low levels of IP 3 , caused dissociation of Irbit from IP 3 Rs and allowed translocation of Irbit to CFTR and SLC26A6 in the plasma membrane. These processes stimulated epithelial secretion of electrolytes and fluid. These pathways were not observed in pancreatic and salivary glands from Irbit −/− or SLC26A6 −/− mice, or in salivary gland ducts expressing mutant forms of IP 3 Rs that could not undergo protein kinase A–mediated phosphorylation. Conclusions Irbit promotes synergy between the Ca 2+ and cAMP signaling pathways in cultured cells and in pancreatic and salivary ducts from mice. Defects in this pathway could be involved in cystic fibrosis, pancreatitis, or Sjogren syndrome.
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solute carrier family 26 member a2 slc26a2 protein functions as an electroneutral so42 oh cl exchanger regulated by extracellular cl
Journal of Biological Chemistry, 2012Co-Authors: Ehud Ohana, Nikolay Shcheynikov, Meeyoung Park, Shmuel MuallemAbstract:Slc26a2 is a ubiquitously expressed SO42− transporter with high expression levels in cartilage and several epithelia. Mutations in SLC26A2 are associated with diastrophic dysplasia. The mechanism by which Slc26a2 transports SO42− and the ion gradients that mediate SO42− uptake are poorly understood. We report here that Slc26a2 functions as an SO42−/2OH−, SO42−/2Cl−, and SO42−/OH−/Cl− exchanger, depending on the Cl− and OH− gradients. At inward Cl− and outward pH gradients (high Cl−o and low pHo) Slc26a2 functions primarily as an SO42−o/2OH−i exchanger. At low Cl−o and high pHo Slc26a2 functions increasingly as an SO42−o/2Cl−i exchanger. The reverse is observed for SO42−i/2OH−o and SO42−i/2Cl−o exchange. Slc26a2 also exchanges Cl− for I−, Br−, and NO3− and Cl−o competes with SO42− on the transport site. Interestingly, Slc26a2 is regulated by an extracellular anion site, required to activate SO42−i/2OH−o exchange. Slc26a2 can transport oxalate in exchange for OH− and/or Cl− with properties similar to SO42− transport. Modeling of the Slc26a2 transmembrane domain (TMD) structure identified a conserved extracellular sequence 367GFXXP371 between TMD7 and TMD8 close to the conserved Glu417 in the permeation pathway. Mutation of Glu417 eliminated transport by Slc26a2, whereas mutation of Phe368 increased the affinity for SO42−o 8-fold while reducing the affinity for Cl−o 2 fold, but without affecting regulation by Cl−o. These findings clarify the mechanism of net SO42− transport and describe a novel regulation of Slc26a2 by an extracellular anion binding site and should help in further understanding aberrant SLC26A2 function in diastrophic dysplasia.
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diverse transport modes by the solute carrier 26 family of anion transporters
The Journal of Physiology, 2009Co-Authors: Ehud Ohana, Nikolay Shcheynikov, Dongki Yang, Shmuel MuallemAbstract:The solute carrier 26 (SLC26) transporters are anion transporters with diverse substrate specificity. Several members are ubiquitous while others show limited tissue distribution. They are expressed in many epithelia and to the extent known, play a central role in anion secretion and absorption. Members of the family are primarily Cl- transporters, although some members transport mainly SO(4)2-, Cl-, HCO(3)- or I-. A defining feature of the family is their functional diversity. Slc26a1 and Slc26a2 function as specific SO(4)2- transporters while Slc26a4 functions as an electroneutral Cl-/I-/HCO(3)- exchanger. Slc26a3 and SLC26A6 function as coupled electrogenic Cl-/HCO(3)- exchangers or as bona fide anion channels. SLC26A7 and SLC26A9 function exclusively as Cl- channels. This short review discusses the functional diversity of the SLC26 transporters.
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the slc26a4 transporter functions as an electroneutral cl i hco3 exchanger role of slc26a4 and SLC26A6 in i and hco3 secretion and in regulation of cftr in the parotid duct
The Journal of Physiology, 2008Co-Authors: Nikolay Shcheynikov, Lawrence P. Karniski, Dongki Yang, Youxue Wang, Weizong Zeng, Insuk So, Shmuel MuallemAbstract:Transcellular Cl− and HCO3− transport is a vital function of secretory epithelia and exit across the luminal membrane is mediated by members of the SLC26 transporters in conjunction with cystic fibrosis transmembrane conductance regulator (CFTR) channel. Typically, secretory epithelia express several SLC26 transporters in the same tissue; however, how their specific function is determined in vivo is not known. In the present work we used the parotid gland duct which expressed Slc26a4 and SLC26A6 and the model systems of Slc26a4−/− and SLC26A6−/− mice to study the role and regulation of these SLC26 transporters. We examined the transport modes of SLC26A4 expressed in Xenopus oocytes and report that SLC26A4 functions as a coupled, electroneutral I−/Cl−, I−/HCO3− and Cl−/HCO3− exchanger with 1: 1 stoichiometry, with I− as the preferred anion. In the duct, Slc26a4 is expressed in the luminal membrane and mainly mediates I− secretion with minimal role in luminal HCO3− transport. By contrast, SLC26A6 mediates luminal Cl−/HCO3− exchange activity with minimal role in I− secretion. Furthermore, silencing of CFTR altered Cl−/HCO3− exchange by SLC26A6, but had no effect on I− secretion by Slc26a4. Accordingly, deletion of SLC26A6, but not deletion of Slc26a4, results in dysregulation of CFTR. These findings provide the first evidence for a selective role of the SLC26 transporters expressed in the same tissue in epithelial anion transport and suggest that transport specificity is achieved by both the properties of the transporters and the composition of the complexes they form.
Elma El Khouri - One of the best experts on this subject based on the ideXlab platform.
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slc26a3 deficiency is associated with epididymis dysplasia and impaired sperm fertilization potential in the mouse
Molecular Reproduction and Development, 2018Co-Authors: Brigitte Riederer, Elma El Khouri, Marjorie Whitfield, Laurence Stouvenel, Archana Kini, Patrick LoresAbstract:Members of the solute carrier 26 (SLC26) family have emerged as important players in mediating anions fluxes across the plasma membrane of epithelial cells, in cooperation with the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Among them, SLC26A3 acts as a chloride/bicarbonate exchanger, highly expressed in the gastrointestinal, pancreatic and renal tissues. In humans, mutations in the SLC26A3 gene were shown to induce congenital chloride-losing diarrhea (CLD), a rare autosomal recessive disorder characterized by life-long secretory diarrhea. In view of some reports indicating subfertility in some male CLD patients together with SLC26-A3 and -A6 expression in the male genital tract and sperm cells, we analyzed the male reproductive parameters and functions of SLC26A3 deficient mice, which were previously reported to display CLD gastro-intestinal features. We show that in contrast to SLC26A6, deletion of Slc26a3 is associated with severe lesions and abnormal cytoarchitecture of the epididymis, together with sperm quantitative, morphological and functional defects, which altogether compromised male fertility. Overall, our work provides new insight into the pathophysiological mechanisms that may alter the reproductive functions and lead to male subfertility in CLD patients, with a phenotype reminiscent of that induced by CFTR deficiency in the male genital tract.
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functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the slc26 family of anion transporters slc26a8 and slc26a9 physiological and pathophysiological relevance
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Elma El Khouri, Aminata ToureAbstract:The solute carrier 26 (SLC26) proteins are transmembrane proteins located at the plasma membrane of the cells and transporting a variety of monovalent and divalent anions, including chloride, bicarbonate, sulfate and oxalate. In humans, 11 members have been identified (SLC26A1 to SLC26A11) and although part of them display a very restricted tissue expression pattern, altogether they are widely expressed in the epithelial cells of the body where they contribute to the composition and the pH regulation of the secreted fluids. Importantly, mutations in SLC26A2, A3, A4, and A5 have been associated with distinct human genetic recessive disorders (i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues. During the last decade, physical and functional interactions of SLC26 members with the cystic fibrosis transmembrane conductance regulator (CFTR) have been highly documented, leading to the model of a crosstalk based on the binding of the SLC26 STAS domain to the CFTR regulatory domain. In this review, we will focus on the functional interaction of SLC26A8 and SLC26A9 with the CFTR channel. In particular we will highlight the newly published studies indicating that mutations in SLC26A8 and SLC26A9 proteins are associated with a deregulation of the CFTR anion transport activity in the pathophysiological context of the sperm and the pulmonary cells. These studies confirm the physiological relevance of SLC26 and CFTR cross-regulation, opening new gates for the treatment of cystic fibrosis.
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functional interaction of the cystic fibrosis transmembrane conductance regulator with members of the slc26 family of anion transporters slc26a8 and slc26a9 physiological and pathophysiological relevance
The International Journal of Biochemistry & Cell Biology, 2014Co-Authors: Elma El Khouri, Aminata ToureAbstract:Abstract The solute carrier 26 (SLC26) proteins are transmembrane proteins located at the plasma membrane of the cells and transporting a variety of monovalent and divalent anions, including chloride, bicarbonate, sulfate and oxalate. In humans, 11 members have been identified (SLC26A1 to SLC26A11) and although part of them display a very restricted tissue expression pattern, altogether they are widely expressed in the epithelial cells of the body where they contribute to the composition and the pH regulation of the secreted fluids. Importantly, mutations in SLC26A2 , A3 , A4 , and A5 have been associated with distinct human genetic recessive disorders ( i.e. diastrophic dysplasia, congenital chloride diarrhea, Pendred syndrome and deafness, respectively), demonstrating their essential and non-redundant functions in many tissues. During the last decade, physical and functional interactions of SLC26 members with the cystic fibrosis transmembrane conductance regulator (CFTR) have been highly documented, leading to the model of a crosstalk based on the binding of the SLC26 STAS domain to the CFTR regulatory domain. In this review, we will focus on the functional interaction of SLC26A8 and SLC26A9 with the CFTR channel. In particular we will highlight the newly published studies indicating that mutations in SLC26A8 and SLC26A9 proteins are associated with a deregulation of the CFTR anion transport activity in the pathophysiological context of the sperm and the pulmonary cells. These studies confirm the physiological relevance of SLC26 and CFTR cross-regulation, opening new gates for the treatment of cystic fibrosis. This article is part of a Directed Issue entitled: Cystic Fibrosis: From o-mics to cell biology, physiology, and therapeutic advances.
Zhirong Jiang - One of the best experts on this subject based on the ideXlab platform.
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loss of cystic fibrosis transmembrane regulator impairs intestinal oxalate secretion
Journal of The American Society of Nephrology, 2017Co-Authors: Felix Knauf, Zhirong Jiang, John F Heneghan, John R Asplin, Robert B Thomson, Adedotun Adebamiro, Claire L Thomson, Christina Barone, Marie E EganAbstract:Patients with cystic fibrosis have an increased incidence of hyperoxaluria and calcium oxalate nephrolithiasis. Net intestinal absorption of dietary oxalate results from passive paracellular oxalate absorption as modified by oxalate back secretion mediated by the SLC26A6 oxalate transporter. We used mice deficient in the cystic fibrosis transmembrane conductance regulator gene (Cftr) to test the hypothesis that SLC26A6-mediated oxalate secretion is defective in cystic fibrosis. We mounted isolated intestinal tissue from C57BL/6 (wild-type) and Cftr-/- mice in Ussing chambers and measured transcellular secretion of [14C]oxalate. Intestinal tissue isolated from Cftr-/- mice exhibited significantly less transcellular oxalate secretion than intestinal tissue of wild-type mice. However, glucose absorption, another representative intestinal transport process, did not differ in Cftr-/- tissue. Compared with wild-type mice, Cftr-/- mice showed reduced expression of SLC26A6 in duodenum by immunofluorescence and Western blot analysis. Furthermore, coexpression of CFTR stimulated SLC26A6-mediated Cl--oxalate exchange in Xenopus oocytes. In association with the profound defect in intestinal oxalate secretion, Cftr-/- mice had serum and urine oxalate levels 2.5-fold greater than those of wild-type mice. We conclude that defective intestinal oxalate secretion mediated by SLC26A6 may contribute to the hyperoxaluria observed in this mouse model of cystic fibrosis. Future studies are needed to address whether similar mechanisms contribute to the increased risk for calcium oxalate stone formation observed in patients with cystic fibrosis.
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Urinary Metabolic Phenotyping the SLC26A6 (Chloride–Oxalate Exchanger) Null Mouse Model
2016Co-Authors: Isabel Garcia-perez, Zhirong Jiang, Alma Villaseñor, Anisha Wijeyesekera, Joram M. Posma, Jeremiah Stamler, Peter Aronson, Robert Unwin, Coral Barbas, Paul ElliottAbstract:The prevalence of renal stone disease is increasing, although it remains higher in men than in women when matched for age. While still somewhat controversial, several studies have reported an association between renal stone disease and hypertension, but this may be confounded by a shared link with obesity. However, independent of obesity, hyperoxaluria has been shown to be associated with hypertension in stone-formers, and the most common type of renal stone is composed of calcium oxalate. The chloride–oxalate exchanger SLC26A6 (also known as CFEX or PAT-1), located in the renal proximal tubule, was originally thought to have an important role in sodium homeostasis and thereby blood pressure control, but it has recently been shown to have a key function in oxalate balance by mediating oxalate secretion in the gut. We have applied two orthogonal analytical platforms (NMR spectroscopy and capillary electrophoresis with UV detection) in parallel to characterize the urinary metabolic signatures related to the loss of the renal chloride–oxalate exchanger in SLC26A6 null mice. Clear metabolic differentiation between the urinary profiles of the SLC26A6 null and the wild type mice were observed using both methods, with the combination of NMR and CE-UV providing extensive coverage of the urinary metabolome. Key discriminating metabolites included oxalate, m-hydroxyphenylpropionylsulfate (m-HPPS), trimethylamine-N-oxide, glycolate and scyllo-inositol (higher in SLC26A6 null mice) and hippurate, taurine, trimethylamine, and citrate (lower in SLC26A6 null mice). In addition to the reduced efficiency of anion transport, several of these metabolites (hippurate, m-HPPS, methylamines) reflect alteration in gut microbial cometabolic activities. Gender-related metabotypes were also observed in both wild type and SLC26A6 null groups. Urinary metabolites that showed a sex-specific pattern included trimethylamine, trimethylamine-N-oxide, citrate, spermidine, guanidinoacetate, and 2-oxoisocaproate. The gender-dependent metabolic expression of the consequences of SLC26A6 deletion might have relevance to the difference in prevalence of renal stone formation in men and women. The different composition of microbial metabolites in the SLC26A6 null mice is consistent with the fact that the SLC26A6 transporter is found in a range of tissues, including the kidney and intestine, and provides further evidence for the “long reach” of the microbiota in physiological and pathological processes
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urinary metabolic phenotyping the SLC26A6 chloride oxalate exchanger null mouse model
Journal of Proteome Research, 2012Co-Authors: Isabel Garciaperez, Zhirong Jiang, Peter S Aronson, Anisha Wijeyesekera, Joram M. Posma, Jeremiah Stamler, Coral Barbas, Alma Villasenor, R J Unwin, Paul ElliottAbstract:The prevalence of renal stone disease is increasing, although it remains higher in men than in women when matched for age. While still somewhat controversial, several studies have reported an association between renal stone disease and hypertension, but this may be confounded by a shared link with obesity. However, independent of obesity, hyperoxaluria has been shown to be associated with hypertension in stone-formers and the most common type of renal stone is composed of calcium oxalate. The chloride-oxalate exchanger SLC26A6 (also known as CFEX or PAT-1), located in the renal proximal tubule, was originally thought to have an important role in sodium homeostasis and thereby blood pressure control, but it has recently been shown to have a key function in oxalate balance by mediating oxalate secretion in the gut. We have applied two orthogonal analytical platforms (NMR spectroscopy and capillary-electrophoresis with UV detection) in parallel to characterize the urinary metabolic signatures related to the loss of the renal chloride-oxalate exchanger in SLC26A6 null mice. Clear metabolic differentiation between the urinary profiles of the SLC26A6 null and the wild type mice were observed using both methods, with the combination of NMR and CE-UV providing extensive coverage of the urinary metabolome. Key discriminating metabolites included oxalate, m-hydroxyphenylpropionylsulfate (m-HPPS), trimethylamine-N-oxide, glycolate and scyllo-inositol (higher in SLC26A6 null mice) and hippurate, taurine, trimethylamine, and citrate (lower in SLC26A6 null mice). In addition to the reduced efficiency of anion transport, several of these metabolites (hippurate, m-HPPS, methylamines) reflect alteration in gut microbial co-metabolic activities. Gender-related metabotypes were also observed in both wild type and SLC26A6 null groups. Other urinary chemicals that showed a gender-specific pattern included trimethylamine, trimethylamine-N-oxide, citrate, spermidine, guanidinoacetate, and 2-oxoisocaproate. The gender-dependent metabolic expression of the consequences of SLC26A6 deletion might have relevance to the difference in prevalence of renal stone formation in men and women. The modification of the microbial metabolites is consistent with the fact that the SLC26A6 transporter is found in a range of tissues, including the kidney and intestine, and provides further evidence for the ‘long reach’ of the microbiota in physiological and pathological processes.
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phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis
American Journal of Kidney Diseases, 2008Co-Authors: Adam B Weinstein, Dawn S Milliner, Julie B Olson, Andrea G Cogal, Zhirong Jiang, Audrey L Rohlinger, Beth B Bjornson, Eric J Bergstralh, Peter S AronsonAbstract:Background Urinary oxalate is a major risk factor for calcium oxalate stones. Marked hyperoxaluria arises from mutations in 2 separate loci, AGXT and GRHPR , the causes of primary hyperoxaluria (PH) types 1 (PH1) and 2 (PH2), respectively. Studies of null SLC26A6 −/− mice have shown a phenotype of hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis, leading to the hypothesis that SLC26A6 mutations may cause or modify hyperoxaluria in humans. Study Design Cross-sectional case-control. Setting & Participants Cases were recruited from the International Primary Hyperoxaluria Registry. Control DNA samples were from a pool of adult subjects who identified themselves as being in good health. Predictor PH1, PH2, and non-PH1/PH2 genotypes in cases. Outcomes & Measures Homozygosity or compound heterozygosity for SLC26A6 variants. Functional expression of oxalate transport in Xenopus laevis oocytes. Results 80 PH1, 6 PH2, 8 non-PH1/PH2, and 96 control samples were available for SLC26A6 screening. A rare variant, c.487C→T (p.Pro163Ser), was detected solely in 1 non-PH1/PH2 pedigree, but this variant failed to segregate with hyperoxaluria, and functional studies of oxalate transport in Xenopus oocytes showed no transport defect. No other rare variant was identified specifically in non-PH1/PH2. Six additional missense variants were detected in controls and cases. Of these, c.616G→A (p.Val206Met) was most common (11%) and showed a 30% reduction in oxalate transport. To test p.Val206Met as a potential modifier of hyperoxaluria, we extended screening to PH1 and PH2. Heterozygosity for this variant did not affect plasma or urine oxalate levels in this population. Limitations We did not have a sufficient number of cases to determine whether homozygosity for p.Val206Met might significantly affect urine oxalate. Conclusions SLC26A6 was effectively ruled out as the disease gene in this non-PH1/PH2 cohort. Taken together, our studies are the first to identify and characterize SLC26A6 variants in patients with hyperoxaluria. Phenotypic and functional analysis excluded a significant effect of identified variants on oxalate excretion.
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calcium oxalate urolithiasis in mice lacking anion transporter SLC26A6
Nature Genetics, 2006Co-Authors: Zhirong Jiang, Vazhaikkurichi M. Rajendran, John R Asplin, Heino Velazquez, Timothy Nottoli, Henry J Binder, Peter S AronsonAbstract:Urolithiasis is one of the most common urologic diseases in industrialized societies. Calcium oxalate is the predominant component in 70–80% of kidney stones1, and small changes in urinary oxalate concentration affect the risk of stone formation2. SLC26A6 is an anion exchanger expressed on the apical membrane in many epithelial tissues, including kidney and intestine3,4,5,6. Among its transport activities, SLC26A6 mediates Cl−-oxalate exchange5,6,7,8,9. Here we show that mutant mice lacking SLC26A6 develop a high incidence of calcium oxalate urolithiasis. SLC26A6-null mice have significant hyperoxaluria and elevation in plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction. In vitro flux studies indicated that mice lacking SLC26A6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate. We conclude that the anion exchanger SLC26A6 has a major constitutive role in limiting net intestinal absorption of oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis.