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Pflugers Arch
2023 Feb 01;4752:249-266. doi: 10.1007/s00424-022-02742-3.
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Oxalate secretion is stimulated by a cAMP-dependent pathway in the mouse cecum.
Whittamore JM
,
Hatch M
.
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Elevated levels of the intracellular second messenger cAMP can stimulate intestinal oxalate secretion however the membrane transporters responsible are unclear. Oxalate transport by the chloride/bicarbonate (Cl-/HCO3-) exchanger Slc26a6 or PAT-1 (Putative Anion Transporter 1), is regulated via cAMP when expressed in Xenopus oocytes and cultured cells but whether this translates to the native epithelia is unknown. This study investigated the regulation of oxalate transport by the mouse intestine focusing on transport at the apical membrane hypothesizing PAT-1 is the target of a cAMP-dependent signaling pathway. Adopting the Ussing chamber technique we measured unidirectional 14C-oxalate and 36Cl- flux ([Formula: see text] and [Formula: see text]) across distal ileum, cecum and distal colon, employing forskolin (FSK) and 3-isobutyl-1-methylxanthine (IBMX) to trigger cAMP production. FSK/IBMX initiated a robust secretory response by all segments but the stimulation of net oxalate secretion was confined to the cecum only involving activation of [Formula: see text] and distinct from net Cl- secretion produced by inhibiting [Formula: see text]. Using the PAT-1 knockout (KO) mouse we determined cAMP-stimulated [Formula: see text] was not directly dependent on PAT-1, but it was sensitive to mucosal DIDS (4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid), although unlikely to be another Cl-/HCO3- exchanger given the lack of trans-stimulation or cis-inhibition by luminal Cl- or HCO3-. The cAMP-activated oxalate efflux was reliant on CFTR (Cystic Fibrosis Transmembrane conductance Regulator) activity, but only in the presence of PAT-1, leading to speculation on the involvement of a multi-transporter regulatory complex. Further investigations at the cellular and molecular level are necessary to define the mechanism and transporter(s) responsible.
Alper,
Native and recombinant Slc26a3 (downregulated in adenoma, Dra) do not exhibit properties of 2Cl-/1HCO3- exchange.
2011, Pubmed,
Xenbase
Alper,
Native and recombinant Slc26a3 (downregulated in adenoma, Dra) do not exhibit properties of 2Cl-/1HCO3- exchange.
2011,
Pubmed
,
Xenbase
Arike,
Protein Turnover in Epithelial Cells and Mucus along the Gastrointestinal Tract Is Coordinated by the Spatial Location and Microbiota.
2020,
Pubmed
Arvans,
Oxalobacter formigenes-Derived Bioactive Factors Stimulate Oxalate Transport by Intestinal Epithelial Cells.
2017,
Pubmed
Arvans,
Activation of the PKA signaling pathway stimulates oxalate transport by human intestinal Caco2-BBE cells.
2020,
Pubmed
Asplin,
Hyperoxaluric calcium nephrolithiasis.
2002,
Pubmed
Barmeyer,
Characteristics of rat downregulated in adenoma (rDRA) expressed in HEK 293 cells.
2007,
Pubmed
Cabantchik,
Chemical probes for anion transporters of mammalian cell membranes.
1992,
Pubmed
Canales,
Oxalobacter formigenes colonization normalizes oxalate excretion in a gastric bypass model of hyperoxaluria.
2017,
Pubmed
Chernova,
Functional comparison of mouse slc26a6 anion exchanger with human SLC26A6 polypeptide variants: differences in anion selectivity, regulation, and electrogenicity.
2005,
Pubmed
,
Xenbase
Chernova,
Acute regulation of the SLC26A3 congenital chloride diarrhoea anion exchanger (DRA) expressed in Xenopus oocytes.
2003,
Pubmed
,
Xenbase
Cil,
SLC26A6-selective inhibitor identified in a small-molecule screen blocks fluid absorption in small intestine.
2021,
Pubmed
Clarke,
Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis.
1992,
Pubmed
Clarke,
CFTR is required for cAMP inhibition of intestinal Na+ absorption in a cystic fibrosis mouse model.
1996,
Pubmed
Costello,
Extrarenal clearance of oxalate increases with progression of renal failure in the rat.
1992,
Pubmed
Eckman,
Dietary changes improve survival of CFTR S489X homozygous mutant mouse.
1995,
Pubmed
El Khouri,
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.
2014,
Pubmed
Forlino,
A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype.
2005,
Pubmed
Freel,
Enteric oxalate secretion is not directly mediated by the human CFTR chloride channel.
2008,
Pubmed
,
Xenbase
Freel,
Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6 null mice.
2006,
Pubmed
Freel,
Transcellular oxalate and Cl- absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate.
2013,
Pubmed
Freel,
Parsing apical oxalate exchange in Caco-2BBe1 monolayers: siRNA knockdown of SLC26A6 reveals the role and properties of PAT-1.
2009,
Pubmed
Freel,
Conductive pathways for chloride and oxalate in rabbit ileal brush-border membrane vesicles.
1998,
Pubmed
Frizzell,
Physiology of epithelial chloride and fluid secretion.
2012,
Pubmed
Haila,
SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types.
2001,
Pubmed
Hästbacka,
The diastrophic dysplasia gene encodes a novel sulfate transporter: positional cloning by fine-structure linkage disequilibrium mapping.
1994,
Pubmed
Hatch,
Alterations in intestinal transport of oxalate in disease states.
1995,
Pubmed
Hatch,
Mechanisms of oxalate absorption and secretion across the rabbit distal colon.
1994,
Pubmed
Hatch,
Angiotensin II involvement in adaptive enteric oxalate excretion in rats with chronic renal failure induced by hyperoxaluria.
2003,
Pubmed
Hatch,
Renal and intestinal handling of oxalate following oxalate loading in rats.
2003,
Pubmed
Hatch,
Intestinal transport of an obdurate anion: oxalate.
2005,
Pubmed
Hatch,
A human strain of Oxalobacter (HC-1) promotes enteric oxalate secretion in the small intestine of mice and reduces urinary oxalate excretion.
2013,
Pubmed
Hatch,
Oxalobacter sp. reduces urinary oxalate excretion by promoting enteric oxalate secretion.
2006,
Pubmed
Hatch,
Enteric oxalate elimination is induced and oxalate is normalized in a mouse model of primary hyperoxaluria following intestinal colonization with Oxalobacter.
2011,
Pubmed
Hatch,
Induction of enteric oxalate secretion by Oxalobacter formigenes in mice does not require the presence of either apical oxalate transport proteins Slc26A3 or Slc26A6.
2020,
Pubmed
Hatch,
Intestinal excretion of oxalate in chronic renal failure.
1994,
Pubmed
Hatch,
Characteristics of the transport of oxalate and other ions across rabbit proximal colon.
1993,
Pubmed
Hayashi,
Segmental differences in Slc26a3-dependent Cl- absorption and HCO3- secretion in the mouse large intestine in vitro in Ussing chambers.
2021,
Pubmed
Heneghan,
Regulated transport of sulfate and oxalate by SLC26A2/DTDST.
2010,
Pubmed
,
Xenbase
Homaidan,
Ion transport across the cecum in normal and colitic mice.
1999,
Pubmed
Jacob,
Down-regulated in adenoma mediates apical Cl-/HCO3- exchange in rabbit, rat, and human duodenum.
2002,
Pubmed
Jiang,
Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6.
2006,
Pubmed
Karaica,
Sex-independent expression of chloride/formate exchanger Cfex (Slc26a6) in rat pancreas, small intestine, and liver, and male-dominant expression in kidneys.
2018,
Pubmed
Kato,
Regulation of electroneutral NaCl absorption by the small intestine.
2011,
Pubmed
Keely,
Intestinal secretory mechanisms and diarrhea.
2022,
Pubmed
Knauf,
Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion.
2017,
Pubmed
,
Xenbase
Ko,
A molecular mechanism for aberrant CFTR-dependent HCO(3)(-) transport in cystic fibrosis.
2002,
Pubmed
Ko,
Gating of CFTR by the STAS domain of SLC26 transporters.
2004,
Pubmed
Lamprecht,
Transport properties of the human intestinal anion exchanger DRA (down-regulated in adenoma) in transfected HEK293 cells.
2005,
Pubmed
Lamprecht,
Regulation of the intestinal anion exchanger DRA (downregulated in adenoma).
2009,
Pubmed
Liu,
Short-Chain Fatty Acids Reduced Renal Calcium Oxalate Stones by Regulating the Expression of Intestinal Oxalate Transporter SLC26A6.
2021,
Pubmed
Ma,
Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion.
2002,
Pubmed
Melvin,
Mouse down-regulated in adenoma (DRA) is an intestinal Cl(-)/HCO(3)(-) exchanger and is up-regulated in colon of mice lacking the NHE3 Na(+)/H(+) exchanger.
1999,
Pubmed
Musch,
Functional coupling of the downregulated in adenoma Cl-/base exchanger DRA and the apical Na+/H+ exchangers NHE2 and NHE3.
2009,
Pubmed
Ohana,
Solute carrier family 26 member a2 (Slc26a2) protein functions as an electroneutral SOFormula/OH-/Cl- exchanger regulated by extracellular Cl-.
2012,
Pubmed
,
Xenbase
Park,
Multiple roles of the SO4(2-)/Cl-/OH- exchanger protein Slc26a2 in chondrocyte functions.
2014,
Pubmed
Sakhaee,
Clinical review. Kidney stones 2012: pathogenesis, diagnosis, and management.
2012,
Pubmed
Satoh,
Functional analysis of diastrophic dysplasia sulfate transporter. Its involvement in growth regulation of chondrocytes mediated by sulfated proteoglycans.
1998,
Pubmed
,
Xenbase
Schultz,
Pharmacology of CFTR chloride channel activity.
1999,
Pubmed
Seidler,
Sodium and chloride absorptive defects in the small intestine in Slc26a6 null mice.
2008,
Pubmed
Simpson,
Putative anion transporter-1 (Pat-1, Slc26a6) contributes to intracellular pH regulation during H+-dipeptide transport in duodenal villous epithelium.
2010,
Pubmed
Simpson,
PAT-1 (Slc26a6) is the predominant apical membrane Cl-/HCO3- exchanger in the upper villous epithelium of the murine duodenum.
2007,
Pubmed
Simpson,
Chloride conductance of CFTR facilitates basal Cl-/HCO3- exchange in the villous epithelium of intact murine duodenum.
2005,
Pubmed
Singh,
CFTR and its key role in in vivo resting and luminal acid-induced duodenal HCO3- secretion.
2008,
Pubmed
Singh,
Molecular transport machinery involved in orchestrating luminal acid-induced duodenal bicarbonate secretion in vivo.
2013,
Pubmed
Singh,
The switch of intestinal Slc26 exchangers from anion absorptive to HCOFormula secretory mode is dependent on CFTR anion channel function.
2010,
Pubmed
Smith,
Effect of IBMX and alkaline phosphatase inhibitors on Cl- secretion in G551D cystic fibrosis mutant mice.
1998,
Pubmed
Spiegel,
Independence of apical Cl-/HCO3- exchange and anion conductance in duodenal HCO3- secretion.
2003,
Pubmed
Stephens,
125 Iodide as a surrogate tracer for epithelial chloride transport by the mouse large intestine in vitro.
2019,
Pubmed
Stephens,
The role of NHE3 (Slc9a3) in oxalate and sodium transport by mouse intestine and regulation by cAMP.
2021,
Pubmed
Stern,
Fecal transplant modifies urine chemistry risk factors for urinary stone disease.
2019,
Pubmed
Stewart,
SLC26 anion exchangers of guinea pig pancreatic duct: molecular cloning and functional characterization.
2011,
Pubmed
,
Xenbase
Talbot,
Segregation of Na/H exchanger-3 and Cl/HCO3 exchanger SLC26A3 (DRA) in rodent cecum and colon.
2010,
Pubmed
Tse,
cAMP Stimulates SLC26A3 Activity in Human Colon by a CFTR-Dependent Mechanism That Does Not Require CFTR Activity.
2019,
Pubmed
Tuo,
Involvement of the anion exchanger SLC26A6 in prostaglandin E2- but not forskolin-stimulated duodenal HCO3- secretion.
2006,
Pubmed
Walker,
Down-regulated in adenoma Cl/HCO3 exchanger couples with Na/H exchanger 3 for NaCl absorption in murine small intestine.
2008,
Pubmed
Wang,
Renal and intestinal transport defects in Slc26a6-null mice.
2005,
Pubmed
Wang,
Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3- secretion: relevance to cystic fibrosis.
2006,
Pubmed
Whittamore,
The anion exchanger PAT-1 (Slc26a6) does not participate in oxalate or chloride transport by mouse large intestine.
2021,
Pubmed
Whittamore,
Loss of the anion exchanger DRA (Slc26a3), or PAT1 (Slc26a6), alters sulfate transport by the distal ileum and overall sulfate homeostasis.
2017,
Pubmed
Whittamore,
Sulfate secretion and chloride absorption are mediated by the anion exchanger DRA (Slc26a3) in the mouse cecum.
2013,
Pubmed
Worcester,
Nephrolithiasis.
2008,
Pubmed
Xia,
The distinct roles of anion transporters Slc26a3 (DRA) and Slc26a6 (PAT-1) in fluid and electrolyte absorption in the murine small intestine.
2014,
Pubmed
Zegarra-Moran,
CFTR pharmacology.
2017,
Pubmed
