Publications by authors named "Peter S Aronson"

51 Publications

Author Reply to Comment on "Assessment of Plasma Oxalate Concentration in Patients With CKD" by Oka

Kidney Int Rep 2021 Apr 5;6(4):1194-1195. Epub 2021 Mar 5.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

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http://dx.doi.org/10.1016/j.ekir.2021.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071653PMC
April 2021

Assessment of Plasma Oxalate Concentration in Patients With CKD.

Kidney Int Rep 2020 Nov 2;5(11):2013-2020. Epub 2020 Sep 2.

Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.

Introduction: Alterations in oxalate homeostasis are associated with kidney stone disease and progression of chronic kidney disease (CKD). However, accurate measurement of plasma oxalate (P) concentrations in large patient cohorts is challenging as prompt acidification of samples has been deemed necessary. In the present study, we investigated the effects of variations in sample handling on P results and examined an alternative strategy to the established preanalytical procedures.

Methods: The effect of storage time at room temperature (RT) and maintenance of samples at -80°C was tested. P was measured in 1826 patients enrolled in the German Chronic Kidney Disease (GCKD) study, an ongoing multicenter, prospective, observational cohort study.

Results: We demonstrate that P concentrations increased rapidly when samples were maintained at RT. This was most relevant for P <10 μM, as concentrations more than doubled within a few hours. Immediate freezing on dry ice and storage at -80°C provided stable results and allowed postponement of acidification for >1 year. In the patients of the lowest estimated glomerular filtration rate (eGFR) quartile, median P was 2.7 μM (interquartile range [IQR] <2.0-4.2) with a median eGFR of 25.1 ml/min per 1.73 m (IQR 20.3-28.1).

Conclusion: We conclude that immediate freezing and maintenance of plasma samples at -80°C facilitates the sample collection process and allows accurate P assessment in large cohorts. The present study may serve as a reference for sample handling to assess P in clinical trials and to determine its role in CKD progression.
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http://dx.doi.org/10.1016/j.ekir.2020.08.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609998PMC
November 2020

Enteric Oxalate Secretion Mediated by Slc26a6 Defends against Hyperoxalemia in Murine Models of Chronic Kidney Disease.

J Am Soc Nephrol 2020 09 13;31(9):1987-1995. Epub 2020 Jul 13.

Department of Internal Medicine, Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut

Background: A state of oxalate homeostasis is maintained in patients with healthy kidney function. However, as GFR declines, plasma oxalate (P) concentrations start to rise. Several groups of researchers have described augmentation of oxalate secretion in the colon in models of CKD, but the oxalate transporters remain unidentified. The oxalate transporter Slc26a6 is a candidate for contributing to the extrarenal clearance of oxalate the gut in CKD.

Methods: Feeding a diet high in soluble oxalate or weekly injections of aristolochic acid induced CKD in age- and sex-matched wild-type and mice. qPCR, immunohistochemistry, and western blot analysis assessed intestinal expression. An oxalate oxidase assay measured fecal and P concentrations.

Results: Fecal oxalate excretion was enhanced in wild-type mice with CKD. This increase was abrogated in mice associated with a significant elevation in plasma oxalate concentration. mRNA and protein expression were greatly increased in the intestine of mice with CKD. Raising P without inducing kidney injury did not alter intestinal expression, suggesting that changes associated with CKD regulate transporter expression rather than elevations in P.

Conclusions: Slc26a6-mediated enteric oxalate secretion is critical in decreasing the body burden of oxalate in murine CKD models. Future studies are needed to address whether similar mechanisms contribute to intestinal oxalate elimination in humans to enhance extrarenal oxalate clearance.
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http://dx.doi.org/10.1681/ASN.2020010105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461683PMC
September 2020

Characterization of renal NaCl and oxalate transport in Slc26a6 mice.

Am J Physiol Renal Physiol 2019 01 14;316(1):F128-F133. Epub 2018 Nov 14.

Department of Internal Medicine, Yale University School of Medicine , New Haven, Connecticut.

The apical membrane Cl/oxalate exchanger SLC26A6 has been demonstrated to play a role in proximal tubule NaCl transport based on studies in microperfused tubules. The present study is directed at characterizing the role of SLC26A6 in NaCl homeostasis in vivo under physiological conditions. Free-flow micropuncture studies revealed that volume and Cl absorption were similar in surface proximal tubules of wild-type and Slc26a6 mice. Moreover, the increments in urine flow rate and sodium excretion following thiazide and furosemide infusion were identical in wild-type and Slc26a6 mice, indicating no difference in NaCl delivery out of the proximal tubule. The absence of an effect of deletion of SLC26A6 on NaCl homeostasis was further supported by the absence of lower blood pressure in Slc26a6 compared with wild-type mice on normal or low-salt diets. Moreover, raising plasma and urine oxalate by feeding mice a diet enriched in soluble oxalate did not affect mean blood pressure. In contrast to the lack of effect of SLC26A6 deletion on NaCl homeostasis, fractional excretion of oxalate was reduced from 1.6 in wild-type mice to 0.7 in Slc26a6 mice. We conclude that, although SLC26A6 is dispensable for renal NaCl homeostasis, it is required for net renal secretion of oxalate.
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http://dx.doi.org/10.1152/ajprenal.00309.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383200PMC
January 2019

Impact of Regular or Extended Hemodialysis and Hemodialfiltration on Plasma Oxalate Concentrations in Patients With End-Stage Renal Disease.

Kidney Int Rep 2017 Nov 8;2(6):1050-1058. Epub 2017 Jun 8.

Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Introduction: Calcium oxalate supersaturation is regularly exceeded in the plasma of patients with end-stage renal disease (ESRD). Previous reports have indicated that hemodialfiltration (HDF) lowers elevated plasma oxalate (P) concentrations more effectively compared with hemodialysis (HD). We reevaluate the therapeutic strategy for optimized P reduction with advanced dialysis equipment and provide data on the effect of extended treatment time on dialytic oxalate kinetics.

Methods: Fourteen patients with ESRD who underwent HDF 3 times a week for 4 to 4.5 hours (regular HDF; n = 8) or 7 to 7.5 hours (extended HDF; n = 6) were changed to HD for 2 weeks and then back to HDF for another 2 weeks. P was measured at baseline, pre-, mid-, and postdialysis, and 2 hours after completion of the treatment session.

Results: Baseline P for all patients averaged 28.0 ± 7.0 μmol/l. Intradialytic P reduction was approximately 90% and was not significantly different between groups or treatment modes [F(1) = 0.63;  = 0.44]. Mean postdialysis P concentrations were 3.3 ± 1.8 μmol/l. A rebound of 2.1 ± 1.9 μmol/l was observed within 2 hours after dialysis. After receiving 2 weeks of the respective treatment, predialysis P concentrations on HD did not differ significantly from those on HDF [F(1) = 0.21;  = 0.66]. Extended treatment time did not provide any added benefit [F(1) = 0.76;  = 0.40].

Discussion: In contrast to earlier observations, our data did not support a benefit of HDF over HD for P reduction. With new technologies evolving, our results emphasized the need to carefully reevaluate and update traditional therapeutic regimens for optimized uremic toxin removal, including those used for oxalate.
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http://dx.doi.org/10.1016/j.ekir.2017.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5733827PMC
November 2017

N-glycosylation critically regulates function of oxalate transporter SLC26A6.

Am J Physiol Cell Physiol 2016 Dec 28;311(6):C866-C873. Epub 2016 Sep 28.

Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut

The brush border Cl-oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate and is crucial for the maintenance of oxalate homeostasis and the prevention of hyperoxaluria and calcium oxalate nephrolithiasis. Previous in vitro studies have suggested that SLC26A6 is heavily N-glycosylated. N-linked glycosylation is known to critically affect folding, trafficking, and function in a wide variety of integral membrane proteins and could therefore potentially have a critical impact on SLC26A6 function and subsequent oxalate homeostasis. Through a series of enzymatic deglycosylation studies we confirmed that endogenously expressed mouse and human SLC26A6 are indeed glycosylated, that the oligosaccharides are principally attached via N-glycosidic linkage, and that there are tissue-specific differences in glycosylation. In vitro cell culture experiments were then used to elucidate the functional significance of the addition of the carbohydrate moieties. Biotinylation studies of SLC26A6 glycosylation mutants indicated that glycosylation is not essential for cell surface delivery of SLC26A6 but suggested that it may affect the efficacy with which it is trafficked and maintained in the plasma membrane. Functional studies of transfected SLC26A6 demonstrated that glycosylation at two sites in the putative second extracellular loop of SLC26A6 is critically important for chloride-dependent oxalate transport and that enzymatic deglycosylation of SLC26A6 expressed on the plasma membrane of intact cells strongly reduced oxalate transport activity. Taken together, these studies indicated that oxalate transport function of SLC26A6 is critically dependent on glycosylation and that exoglycosidase-mediated deglycosylation of SLC26A6 has the capacity to profoundly modulate SLC26A6 function.
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http://dx.doi.org/10.1152/ajpcell.00171.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5206297PMC
December 2016

Loss of Cystic Fibrosis Transmembrane Regulator Impairs Intestinal Oxalate Secretion.

J Am Soc Nephrol 2017 Jan 16;28(1):242-249. Epub 2016 Jun 16.

Departments of Internal Medicine,

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 [C]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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http://dx.doi.org/10.1681/ASN.2016030279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198290PMC
January 2017

Oxalate, inflammasome, and progression of kidney disease.

Curr Opin Nephrol Hypertens 2016 07;25(4):363-71

aDepartment of Nephrology und Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany bDepartment of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Purpose Of Review: Oxalate is an end product of metabolism excreted via the kidney. Excess urinary oxalate, whether from primary or enteric hyperoxaluria, can lead to oxalate deposition in the kidney. Oxalate crystals are associated with renal inflammation, fibrosis, and progressive renal failure. It has long been known that as the glomerular filtration rate becomes reduced in chronic kidney disease (CKD), there is striking elevation of plasma oxalate. Taken together, these findings raise the possibility that elevation of plasma oxalate in CKD may promote renal inflammation and more rapid progression of CKD independent of primary cause.

Recent Findings: The inflammasome has recently been identified to play a critical role in oxalate-induced renal inflammation. Oxalate crystals have been shown to activate the NOD-like receptor family, pyrin domain containing 3 inflammasome (also known as NALP3, NLRP3, or cryopyrin), resulting in release of IL-1β and macrophage infiltration. Deletion of inflammasome proteins in mice protects from oxalate-induced renal inflammation and progressive renal failure.

Summary: The findings reviewed in this article expand our understanding of the relevance of elevated plasma oxalate levels leading to inflammasome activation. We propose that inhibiting oxalate-induced inflammasome activation, or lowering plasma oxalate, may prevent or mitigate progressive renal damage in CKD, and warrants clinical trials.
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http://dx.doi.org/10.1097/MNH.0000000000000229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891250PMC
July 2016

Oxalate-induced chronic kidney disease with its uremic and cardiovascular complications in C57BL/6 mice.

Am J Physiol Renal Physiol 2016 04 13;310(8):F785-F795. Epub 2016 Jan 13.

Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany;

Chronic kidney disease (CKD) research is limited by the lack of convenient inducible models mimicking human CKD and its complications in experimental animals. We demonstrate that a soluble oxalate-rich diet induces stable stages of CKD in male and female C57BL/6 mice. Renal histology is characterized by tubular damage, remnant atubular glomeruli, interstitial inflammation, and fibrosis, with the extent of tissue involvement depending on the duration of oxalate feeding. Expression profiling of markers and magnetic resonance imaging findings established to reflect inflammation and fibrosis parallel the histological changes. Within 3 wk, the mice reproducibly develop normochromic anemia, metabolic acidosis, hyperkalemia, FGF23 activation, hyperphosphatemia, and hyperparathyroidism. In addition, the model is characterized by profound arterial hypertension as well as cardiac fibrosis that persist following the switch to a control diet. Together, this new model of inducible CKD overcomes a number of previous experimental limitations and should serve useful in research related to CKD and its complications.
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http://dx.doi.org/10.1152/ajprenal.00488.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5504458PMC
April 2016

Cyclic GMP kinase II (cGKII) inhibits NHE3 by altering its trafficking and phosphorylating NHE3 at three required sites: identification of a multifunctional phosphorylation site.

J Biol Chem 2015 Jan 5;290(4):1952-65. Epub 2014 Dec 5.

From the Departments of Physiology and Medicine, Gastroenterology Division, and

The epithelial brush-border Na(+)/H(+) exchanger NHE3 is acutely inhibited by cGKII/cGMP, but how cGKII inhibits NHE3 is unknown. This study tested the hypothesis that cGMP inhibits NHE3 by phosphorylating it and altering its membrane trafficking. Studies were carried out in PS120/NHERF2 and in Caco-2/Bbe cells overexpressing HA-NHE3 and cGKII, and in mouse ileum. NHE3 activity was measured with 2',7'-bis(carboxyethyl)-S-(and 6)carboxyfluorescein acetoxy methylester/fluorometry. Surface NHE3 was determined by cell surface biotinylation. Identification of NHE3 phosphorylation sites was by iTRAQ/LC-MS/MS with TiO2 enrichment and immunoblotting with specific anti-phospho-NHE3 antibodies. cGMP/cGKII rapidly inhibited NHE3, which was associated with reduced surface NHE3. cGMP/cGKII increased NHE3 phosphorylation at three sites (rabbit Ser(554), Ser(607), and Ser(663), equivalent to mouse Ser(552), Ser(605), and Ser(659)), all of which had to be present at the same time for cGMP to inhibit NHE3. NHE3-Ser(663) phosphorylation was not necessary for cAMP inhibition of NHE3. Dexamethasone (4 h) stimulated wild type NHE3 activity and increased surface expression but failed to stimulate NHE3 activity or increase surface expression when NHE3 was mutated to either S663A or S663D. We conclude that 1) cGMP inhibition of NHE3 is associated with phosphorylation of NHE3 at Ser(554), Ser(607), and Ser(663), all of which are necessary for cGMP/cGKII to inhibit NHE3. 2) Dexamethasone stimulates NHE3 by phosphorylation of a single site, Ser(663). The requirement for three phosphorylation sites in NHE3 for cGKII inhibition, and for phosphorylation of one of these sites for dexamethasone stimulation of NHE3, is a unique example of regulation by phosphorylation.
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http://dx.doi.org/10.1074/jbc.M114.590174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4303652PMC
January 2015

Overexpression of pendrin in intercalated cells produces chloride-sensitive hypertension.

J Am Soc Nephrol 2013 Jun 13;24(7):1104-13. Epub 2013 Jun 13.

Faculté de Médecine, Université Paris-Descartes, Paris, France.

Inherited and acquired disorders that enhance the activity of transporters mediating renal tubular Na(+) reabsorption are well established causes of hypertension. It is unclear, however, whether primary activation of an Na(+)-independent chloride transporter in the kidney can also play a pathogenic role in this disease. Here, mice overexpressing the chloride transporter pendrin in intercalated cells of the distal nephron (Tg(B1-hPDS) mice) displayed increased renal absorption of chloride. Compared with normal mice, these transgenic mice exhibited a delayed increase in urinary NaCl and ultimately, developed hypertension when exposed to a high-salt diet. Administering the same sodium intake as NaHCO3 instead of NaCl did not significantly alter BP, indicating that the hypertension in the transgenic mice was chloride-sensitive. Moreover, excessive chloride absorption by pendrin drove parallel absorption of sodium through the epithelial sodium channel ENaC and the sodium-driven chloride/bicarbonate exchanger (Ndcbe), despite an appropriate downregulation of these sodium transporters in response to the expanded vascular volume and hypertension. In summary, chloride transport in the distal nephron can play a primary role in driving NaCl transport in this part of the kidney, and a primary abnormality in renal chloride transport can provoke arterial hypertension. Thus, we conclude that the chloride/bicarbonate exchanger pendrin plays a major role in controlling net NaCl absorption, thereby influencing BP under conditions of high salt intake.
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http://dx.doi.org/10.1681/ASN.2012080787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3699825PMC
June 2013

NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy.

Kidney Int 2013 Nov 5;84(5):895-901. Epub 2013 Jun 5.

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

Oxalate nephropathy with renal failure is caused by multiple disorders leading to hyperoxaluria due to either overproduction of oxalate (primary hyperoxaluria) or excessive absorption of dietary oxalate (enteric hyperoxaluria). To study the etiology of renal failure in crystal-induced kidney disease, we created a model of progressive oxalate nephropathy by feeding mice a diet high in soluble oxalate (high oxalate in the absence of dietary calcium). Renal histology was characterized by intratubular calcium-oxalate crystal deposition with an inflammatory response in the surrounding interstitium. Oxalate nephropathy was not found in mice fed a high oxalate diet that also contained calcium. NALP3, also known as cryopyrin, has been implicated in crystal-associated diseases such as gout and silicosis. Mice fed the diet high in soluble oxalate demonstrated increased NALP3 expression in the kidney. Nalp3-null mice were completely protected from the progressive renal failure and death that occurred in wild-type mice fed the diet high in soluble oxalate. NALP3 deficiency did not affect oxalate homeostasis, thereby excluding differences in intestinal oxalate handling to explain the observed phenotype. Thus, progressive renal failure in oxalate nephropathy results primarily from NALP3-mediated inflammation.
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http://dx.doi.org/10.1038/ki.2013.207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3772982PMC
November 2013

Ezrin is required for the functional regulation of the epithelial sodium proton exchanger, NHE3.

PLoS One 2013 6;8(2):e55623. Epub 2013 Feb 6.

Laboratory of Physiology, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Shizuoka, Japan.

The sodium hydrogen exchanger isoform 3 (NHE3) mediates absorption of sodium, bicarbonate and water from renal and intestinal lumina. This activity is fundamental to the maintenance of a physiological plasma pH and blood pressure. To perform this function NHE3 must be present in the apical membrane of renal tubular and intestinal epithelia. The molecular determinants of this localization have not been conclusively determined, although linkage to the apical actin cytoskeleton through ezrin has been proposed. We set out to evaluate this hypothesis. Functional studies of NHE3 activity were performed on ezrin knockdown mice (Vil2(kd/kd)) and NHE3 activity similar to wild-type animals detected. Interpretation of this finding was difficult as other ERM (ezrin/radixin/moesin) proteins were present. We therefore generated an epithelial cell culture model where ezrin was the only detectable ERM. After knockdown of ezrin expression with siRNA, radixin and moesin expression remained undetectable. Consistent with the animal ultrastructural data, cells lacking ezrin retained an epithelial phenotype but had shortened and thicker microvilli. NHE3 localization was identical to cells transfected with non-targeting siRNA. The attachment of NHE3 to the apical cytoskeleton was unaltered as assessed by fluorescent recovery after photobleaching (FRAP) and the solubility of NHE3 in Triton X-100. Baseline NHE3 activity was unaltered, however, cAMP-dependent inhibition of NHE3 was largely lost even though NHE3 was phosphorylated at serines 552 and 605. Thus, ezrin is not necessary for the apical localization, attachment to the cytoskeleton, baseline activity or cAMP induced phosphrylation of NHE3, but instead is required for cAMP mediated inhibition.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055623PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566197PMC
August 2013

Sat1 is dispensable for active oxalate secretion in mouse duodenum.

Am J Physiol Cell Physiol 2012 Jul 18;303(1):C52-7. Epub 2012 Apr 18.

Section of Nephrology, Dept. of Internal Medicine, Yale School of Medicine, New Haven, CT 06520-8029, USA.

Mice deficient for the apical membrane oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium oxalate stones due to a defect in intestinal oxalate secretion. However, the nature of the basolateral membrane oxalate transport process that operates in series with SLC26A6 to mediate active oxalate secretion in the intestine remains unknown. Sulfate anion transporter-1 (Sat1 or SLC26A1) is a basolateral membrane anion exchanger that mediates intestinal oxalate transport. Moreover, Sat1-deficient mice also have a phenotype of hyperoxalemia, hyperoxaluria, and calcium oxalate stones. We, therefore, tested the role of Sat1 in mouse duodenum, a tissue with Sat1 expression and SLC26A6-dependent oxalate secretion. Although the active secretory flux of oxalate across mouse duodenum was strongly inhibited (>90%) by addition of the disulfonic stilbene DIDS to the basolateral solution, secretion was unaffected by changes in medium concentrations of sulfate and bicarbonate, key substrates for Sat1-mediated anion exchange. Inhibition of intracellular bicarbonate production by acetazolamide and complete removal of bicarbonate from the buffer also produced no change in oxalate secretion. Finally, active oxalate secretion was not reduced in Sat1-null mice. We conclude that a DIDS-sensitive basolateral transporter is involved in mediating oxalate secretion across mouse duodenum, but Sat1 itself is dispensable for this process.
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http://dx.doi.org/10.1152/ajpcell.00385.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404526PMC
July 2012

Net intestinal transport of oxalate reflects passive absorption and SLC26A6-mediated secretion.

J Am Soc Nephrol 2011 Dec 21;22(12):2247-55. Epub 2011 Oct 21.

Section of Nephrology., Department of Internal Medicine, Yale University School of Medicine, P.O. Box 208029, One Gilbert Street, TAC S-255, New Haven, Connecticut 06520-8029, USA.

Mice lacking the oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium-oxalate stones as a result of a defect in intestinal oxalate secretion, but what accounts for the absorptive oxalate flux remains unknown. We measured transepithelial absorption of [(14)C]oxalate simultaneously with the flux of [(3)H]mannitol, a marker of the paracellular pathway, across intestine from wild-type and Slc26a6-null mice. We used the anion transport inhibitor DIDS to investigate other members of the SLC26 family that may mediate transcellular oxalate absorption. Absorptive flux of oxalate in duodenum was similar to mannitol, insensitive to DIDS, and nonsaturable, indicating that it is predominantly passive and paracellular. In contrast, in wild-type mice, secretory flux of oxalate in duodenum exceeded that of mannitol, was sensitive to DIDS, and saturable, indicating transcellular secretion of oxalate. In Slc26a6-null mice, secretory flux of oxalate was similar to mannitol, and no net flux of oxalate occurred. Absorptive fluxes of both oxalate and mannitol varied in parallel in different segments of small and large intestine. In epithelial cell lines, modulation of the charge selectivity of the claudin-based pore pathway did not affect oxalate permeability, but knockdown of the tight-junction protein ZO-1 enhanced permeability to oxalate and mannitol in parallel. Moreover, formation of soluble complexes with cations did not affect oxalate absorption. In conclusion, absorptive oxalate flux occurs through the paracellular "leak" pathway, and net absorption of dietary oxalate depends on the relative balance between absorption and SLC26A6-dependent transcellular secretion.
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http://dx.doi.org/10.1681/ASN.2011040433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3250206PMC
December 2011

Effects of pH on potassium: new explanations for old observations.

J Am Soc Nephrol 2011 Nov 6;22(11):1981-9. Epub 2011 Oct 6.

Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8029, USA.

Maintenance of extracellular K(+) concentration within a narrow range is vital for numerous cell functions, particularly electrical excitability of heart and muscle. Potassium homeostasis during intermittent ingestion of K(+) involves rapid redistribution of K(+) into the intracellular space to minimize increases in extracellular K(+) concentration, and ultimate elimination of the K(+) load by renal excretion. Recent years have seen great progress in identifying the transporters and channels involved in renal and extrarenal K(+) homeostasis. Here we apply these advances in molecular physiology to understand how acid-base disturbances affect serum potassium.
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http://dx.doi.org/10.1681/ASN.2011040414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3231780PMC
November 2011

Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells.

Am J Physiol Cell Physiol 2012 Jan 28;302(1):C46-58. Epub 2011 Sep 28.

Section of Nephrology, Dept. of Medicine, The Univ. of Chicago, 5841 S. Maryland Ave., MC5100, Chicago, IL 60637, USA.

Urolithiasis remains a very common disease in Western countries. Seventy to eighty percent of kidney stones are composed of calcium oxalate, and minor changes in urinary oxalate affect stone risk. Intestinal oxalate secretion mediated by anion exchanger SLC26A6 plays a major constitutive role in limiting net absorption of ingested oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis. Using the relatively selective PKC-δ inhibitor rottlerin, we had previously found that PKC-δ activation inhibits Slc26a6 activity in mouse duodenal tissue. To identify a model system to study physiologic agonists upstream of PKC-δ, we characterized the human intestinal cell line T84. Knockdown studies demonstrated that endogenous SLC26A6 mediates most of the oxalate transport by T84 cells. Cholinergic stimulation with carbachol modulates intestinal ion transport through signaling pathways including PKC activation. We therefore examined whether carbachol affects oxalate transport in T84 cells. We found that carbachol significantly inhibited oxalate transport by T84 cells, an effect blocked by rottlerin. Carbachol also led to significant translocation of PKC-δ from the cytosol to the membrane of T84 cells. Using pharmacological inhibitors, we observed that carbachol inhibits oxalate transport through the M(3) muscarinic receptor and phospholipase C. Utilizing the Src inhibitor PP2 and phosphorylation studies, we found that the observed regulation downstream of PKC-δ is partially mediated by c-Src. Biotinylation studies revealed that carbachol inhibits oxalate transport by reducing SLC26A6 surface expression. We conclude that carbachol negatively regulates oxalate transport by reducing SLC26A6 surface expression in T84 cells through signaling pathways including the M(3) muscarinic receptor, phospholipase C, PKC-δ, and c-Src.
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http://dx.doi.org/10.1152/ajpcell.00075.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328906PMC
January 2012

Role of SLC26A6-mediated Cl⁻-oxalate exchange in renal physiology and pathophysiology.

Authors:
Peter S Aronson

J Nephrol 2010 Nov-Dec;23 Suppl 16:S158-64

Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8029, USA.

Although a major fraction of Cl⁻ reabsorption in the proximal tubule is passive and paracellular, there is an additional component of Cl⁻ transport that is transcellular. A search for possible mechanisms that might mediate Cl⁻ uptake into proximal tubule cells led to the identification of an apical membrane Cl--oxalate exchange activity. Subsequent studies identified anion transporter SLC26A6 as responsible for proximal tubule Cl⁻-oxalate exchange activity. The most striking phenotype in Slc26a6 null mice was calcium oxalate urolithiasis due to hyperoxaluria. Hyperoxalemia and hyperoxaluria in Slc26a6 null mice were found to be caused by defective intestinal back-secretion of ingested oxalate. These findings suggested that inherited or acquired defects in SLC26A6 might lead to hyperoxaluria and increased stone risk, and have motivated studies to characterize the role of SLC26A6 in oxalate homeostasis in patients and in animal models.
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February 2011

The Na+-dependent chloride-bicarbonate exchanger SLC4A8 mediates an electroneutral Na+ reabsorption process in the renal cortical collecting ducts of mice.

J Clin Invest 2010 May 12;120(5):1627-35. Epub 2010 Apr 12.

Centre de recherche des Cordeliers, Université Pierre et Marie Curie, ERL CNRS 7226, INSERM UMRS 872 Equipe 3, Paris, France.

Regulation of sodium balance is a critical factor in the maintenance of euvolemia, and dysregulation of renal sodium excretion results in disorders of altered intravascular volume, such as hypertension. The amiloride-sensitive epithelial sodium channel (ENaC) is thought to be the only mechanism for sodium transport in the cortical collecting duct (CCD) of the kidney. However, it has been found that much of the sodium absorption in the CCD is actually amiloride insensitive and sensitive to thiazide diuretics, which also block the Na-Cl cotransporter (NCC) located in the distal convoluted tubule. In this study, we have demonstrated the presence of electroneutral, amiloride-resistant, thiazide-sensitive, transepithelial NaCl absorption in mouse CCDs, which persists even with genetic disruption of ENaC. Furthermore, hydrochlorothiazide (HCTZ) increased excretion of Na+ and Cl- in mice devoid of the thiazide target NCC, suggesting that an additional mechanism might account for this effect. Studies on isolated CCDs suggested that the parallel action of the Na+-driven Cl-/HCO3- exchanger (NDCBE/SLC4A8) and the Na+-independent Cl-/HCO3- exchanger (pendrin/SLC26A4) accounted for the electroneutral thiazide-sensitive sodium transport. Furthermore, genetic ablation of SLC4A8 abolished thiazide-sensitive NaCl transport in the CCD. These studies establish what we believe to be a novel role for NDCBE in mediating substantial Na+ reabsorption in the CCD and suggest a role for this transporter in the regulation of fluid homeostasis in mice.
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http://dx.doi.org/10.1172/JCI40145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860930PMC
May 2010

ESRD as a window into America's cost crisis in health care.

J Am Soc Nephrol 2009 Oct 3;20(10):2093-7. Epub 2009 Sep 3.

Section of Nephrology, Department of Internal Medicine, Yale University School of Medicine, TAC S-255, New Haven, CT 06520-8029, USA.

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http://dx.doi.org/10.1681/ASN.2009070715DOI Listing
October 2009

Prestin's anion transport and voltage-sensing capabilities are independent.

Biophys J 2009 Apr;96(8):3179-86

Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.

The integral membrane protein prestin, a member of the SLC26 anion transporter family, is responsible for the voltage-driven electromotility of mammalian outer hair cells. It was argued that the evolution of prestin's motor function required a loss of the protein's transport capabilities. Instead, it was proposed that prestin manages only an abortive hemicycle that results in the trapped anion acting as a voltage sensor, to generate the motor's signature gating charge movement or nonlinear capacitance. We demonstrate, using classical radioactive anion ([(14)C]formate and [(14)C]oxalate) uptake studies, that in contrast to previous observations, prestin is able to transport anions. The prestin-dependent uptake of both these anions was twofold that of cells transfected with vector alone, and comparable to SLC26a6, prestin's closest phylogenetic relative. Furthermore, we identify a potential chloride-binding site in which the mutations of two residues (P328A and L326A) preserve nonlinear capacitance, yet negate anion transport. Finally, we distinguish 12 charged residues out of 22, residing within prestin's transmembrane regions, that contribute to unitary charge movement, i.e., voltage sensing. These data redefine our mechanistic concept of prestin.
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http://dx.doi.org/10.1016/j.bpj.2008.12.3948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718310PMC
April 2009

Phenotypic and functional analysis of human SLC26A6 variants in patients with familial hyperoxaluria and calcium oxalate nephrolithiasis.

Am J Kidney Dis 2008 Dec 31;52(6):1096-103. Epub 2008 Oct 31.

Mayo Clinic Hyperoxaluria Center, Division of Nephrology and Hypertension, Departments of Internal Medicine and Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.

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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http://dx.doi.org/10.1053/j.ajkd.2008.07.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2710965PMC
December 2008

Characterization of Na+/H+ exchanger NHE8 in cultured renal epithelial cells.

Am J Physiol Renal Physiol 2007 Sep 20;293(3):F761-6. Epub 2007 Jun 20.

Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8856, USA.

NHE8 is expressed in the apical membrane of the proximal tubule and is predicted to be a Na+/H+ exchanger on the basis of its primary amino acid sequence. Functional characterization of native NHE8 in mammalian cells has not been possible to date. We screened a number of polarized renal cell lines for the plasma membrane Na+/H+ exchangers (NHE1, 2, 3, 4, and 8) and found only NHE1 and NHE8 transcripts in NRK cells by RT-PCR. NHE8 protein is expressed in the apical membrane of NRK cells as demonstrated by immunoblots, confocal fluorescent immunocytochemistry, and immunoelectron microscopy. NHE1, on the other hand, is expressed primarily in the basolateral membrane. Bilateral perfusion of NRK cells grown on permeable supports shows Na+/H+ exchange activity on both the apical and basolateral membranes. NHE8-specific small interfering RNA knocks down NHE8 protein expression but does not affect NHE1 protein levels. Knockdown of NHE8 protein is accompanied by a commensurate reduction in apical NHE activity, without altered basolateral NHE activity. Conversely, transfection of NHE1-specific small interfering RNA knocks down NHE1 protein expression without affecting NHE8 protein levels and reduces basolateral NHE activity without affecting apical NHE activity. NHE8 is the only apical membrane Na+/H+ exchanger in NRK cells. NHE8 activity is Na+ dependent, displaying a cooperative sigmoidal relationship, and is highly sensitive to 5-(N-ethyl-n-isopropyl)-amiloride (EIPA). NRK cells provide a useful system where NHE8 can be studied in its native environment.
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http://dx.doi.org/10.1152/ajprenal.00117.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861566PMC
September 2007

Ontogeny of NHE8 in the rat proximal tubule.

Am J Physiol Renal Physiol 2007 Jul 11;293(1):F255-61. Epub 2007 Apr 11.

Dept. of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, USA.

Proximal tubule bicarbonate reabsorption is primarily mediated via the Na(+)/H(+) exchanger, identified as NHE3 in adults. Previous studies have demonstrated a maturational increase in rat proximal tubule NHE3 expression, with a paucity of NHE3 expression in neonates, despite significant Na(+)-dependent proton secretion. Recently, a novel Na(+)/H(+) antiporter (NHE8) was identified and found to be expressed on the apical membrane of the proximal tubule. To determine whether NHE8 may be the antiporter responsible for proton secretion in neonates, the present study characterized the developmental expression of NHE8 in rat proximal tubules. RNA blots and real-time RT-PCR demonstrated no developmental difference in the mRNA of renal NHE8. Immunoblots, however, demonstrated peak protein abundance of NHE8 in brush border membrane vesicles of 7- and 14-day-old compared with adult rats. In contrast, the level of NHE8 expression in total cortical membrane protein was higher in adults than in neonates. Immunohistochemistry confirmed the presence of NHE8 on the apical membrane of the proximal tubules of neonatal and adult rats. These data demonstrate that NHE8 does undergo maturational changes on the apical membrane of the rat proximal tubule and may account for the Na(+)-dependent proton flux in neonatal proximal tubules.
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http://dx.doi.org/10.1152/ajprenal.00400.2006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119019PMC
July 2007

NHE3 phosphorylation at serines 552 and 605 does not directly affect NHE3 activity.

Am J Physiol Renal Physiol 2007 Jul 4;293(1):F212-8. Epub 2007 Apr 4.

Dept. of Pediatrics, Yale University, New Haven, CT 06520-8064, USA.

Direct phosphorylation of sodium hydrogen exchanger type 3 (NHE3) is a well-established physiological phenomenon; however, the exact role of NHE3 phosphorylation in its regulation remains unclear. The objective of this study was to evaluate whether NHE3 phosphorylation at serines 552 and 605 is physiologically regulated in vivo and, if so, whether changes in phosphorylation at these sites are tightly coupled to changes in transport activity. To this end, we directly compared PKA-induced NHE3 inhibition with site-specific changes in NHE3 phosphorylation in vivo and in vitro. In vivo, PKA was activated using an intravenous infusion of parathyroid hormone in Sprague-Dawley rats. In vitro, PKA was activated directly in opossum kidney (OKP) cells using forskolin and IBMX. NHE3 activity was assayed in microvillar membrane vesicles in the rat model and by (22)Na uptake in the OKP cell model. In both cases, NHE3 phosphorylation at serines 552 and 605 was determined using previously characterized monoclonal phosphospecific antibodies directed to these sites. In vivo, we found dramatic changes in NHE3 phosphorylation at serines 552 and 605 with PKA activation but no corresponding alteration in NHE3 activity. This dissociation between NHE3 phosphorylation and activity was further verified in OKP cells in which phosphorylation clearly preceded transport inhibition. We conclude that although phosphorylation of NHE3 at serines 552 and 605 is regulated by PKA both in vivo and in vitro, phosphorylation of these sites does not directly alter Na(+)/H(+) exchange activity.
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http://dx.doi.org/10.1152/ajprenal.00042.2007DOI Listing
July 2007

Membrane curvature alters the activation kinetics of the epithelial Na+/H+ exchanger, NHE3.

J Biol Chem 2007 Mar 11;282(10):7376-84. Epub 2007 Jan 11.

Department of Pediatrics, Program in Cell Biology, and Program in Computational Biology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.

The epithelial Na(+)/H(+) exchanger, NHE3, was found to activate slowly following an acute cytosolic acidification. The sigmoidal course of activation could not be explained by the conventional two-state model, which postulates that activation results from protonation of an allosteric modifier site. Instead, mathematical modeling predicted the existence of three distinct states of the exchanger: two different inactive states plus an active form. The interconversion of the inactive states is rapid and dependent on pH, whereas the conversion between the second inactive state and the active conformation is slow and pH-independent but subject to regulation by other stimuli. Accordingly, exposure of epithelial cells to hypoosmolar solutions activated NHE3 by accelerating this latter transition. The number of surface-exposed exchangers and their association with the cytoskeleton were not affected by hypoosmolarity. Instead, NHE3 is activated by the membrane deformation, a result of cell swelling. This was suggested by the stimulatory effects of amphiphiles that induce a comparable positive (convex) deformation of the membrane. We conclude that NHE3 exists in multiple states and that different physiological parameters control the transitions between them.
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http://dx.doi.org/10.1074/jbc.M608557200DOI Listing
March 2007

Regulation of anion exchanger Slc26a6 by protein kinase C.

Am J Physiol Cell Physiol 2007 Apr 6;292(4):C1485-92. Epub 2006 Dec 6.

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.

SLC26A6 (CFEX, PAT1) is an anion exchanger expressed in several tissues including renal proximal tubule, pancreatic duct, small intestine, liver, stomach, and heart. It has recently been reported that PKC activation inhibits A6-mediated Cl/HCO(3) exchange by disrupting binding of carbonic anhydrase to A6. However, A6 can operate in HCO(3)-independent exchange modes of physiological importance, as A6-mediated Cl/oxalate exchange plays important roles in proximal tubule NaCl reabsorption and intestinal oxalate secretion. We therefore examined whether PKC activation affects HCO(3)-independent exchange modes of Slc26a6 functionally expressed in Xenopus oocytes. We found that PKC activation inhibited Cl/formate exchange mediated by Slc26a6 but failed to inhibit the related anion exchanger pendrin (SLC26A4) under identical conditions. PKC activation inhibited Slc26a6-mediated Cl/formate exchange, Cl/oxalate exchange, and Cl/Cl exchange to a similar extent. The inhibitor sensitivity profile and the finding that PMA-induced inhibition was calcium independent suggested a potential role for PKC-delta. Indeed, the PKC-delta-selective inhibitor rottlerin significantly blocked PMA-induced inhibition of Slc26a6 activity. Localization of Slc26a6 by immunofluorescence microscopy demonstrated that exposure to PKC activation led to redistribution of Slc26a6 from the oocyte plasma membrane to the intracellular compartment immediately below it. We also observed that PMA decreased the pool of Slc26a6 available to surface biotinylation but had no effect on total Slc26a6 expression. The physiological significance of these findings was supported by the observation that PKC activation inhibited mouse duodenal oxalate secretion, an effect blocked by rottlerin. We conclude that multiple modes of anion exchange mediated by Slc26a6 are negatively regulated by PKC-delta activation.
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http://dx.doi.org/10.1152/ajpcell.00447.2006DOI Listing
April 2007

Role of SLC26-mediated Cl-/base exchange in proximal tubule NaCl transport.

Authors:
Peter S Aronson

Novartis Found Symp 2006 ;273:148-58; discussion 158-63, 261-4

Department of Medicine, Yale University School of Medicine, New Haven, CT 06520-8029, USA.

The majority of the Na+ and Cl- filtered by the kidney is reabsorbed in the proximal tubule. In this nephron segment, a significant fraction of Cl- is transported via apical membrane Cl-/base exchange: Cl-/formate exchange in parallel with Na+/H+ exchange and H+/formate cotransport, and Cl-/oxalate exchange in parallel with oxalate/sulfate exchange and Na+/sulfate cotransport. Apical membrane Cl--OH- or Cl-/HCO3- exchange has also been observed. NHE3 mediates most if not all apical membrane Na+/H+ exchange in the proximal tubule. We evaluated SLC26 family members as candidates to mediate proximal tubule Cl-/base exchange. We could not detect pendrin (SLC26A4) expression in the proximal tubule, and found no change in transtubular NaCl absorption in pendrin null mice. We did find expression of SLC26A6 (CFEX, PAT1) on the apical membrane of proximal tubule cells, and demonstrated that SLC26A6 is capable of mediating the Cl-/base exchange activities described to take place across the brush border membrane. Microperfusion studies on SLC26A6 null mice demonstrated that SLC26A6 is essential for oxalate-dependent NaCl absorption but does not contribute to baseline transport, suggesting it primarily mediates Cl-/oxalate exchange rather than Cl--OH- or Cl-/HCO3- exchange in the proximal tubule. Expression of SLC26A7 was also detected on the brush border membrane of proximal tubule cells. Finally, we demonstrated an essential role for the scaffolding protein PDZK1 in apical membrane expression of SLC26A6.
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February 2007

Specificity and regulation of renal sulfate transporters.

Annu Rev Physiol 2007 ;69:361-75

Department of Physiology and Pharmacology, School of Biomedical Sciences, University of Queensland, Brisbane, QLD 4072 Australia.

Sulfate is essential for normal cellular function. The kidney plays a major role in sulfate homeostasis. Sulfate is freely filtered and then undergoes net reabsorption in the proximal tubule. The apical membrane Na(+)/sulfate cotransporter NaS1 (SLC13A1) has a major role in mediating proximal tubule sulfate reabsorption, as demonstrated by the findings of hyposulfatemia and hypersulfaturia in Nas1-null mice. The anion exchanger SAT1 (SLC26A1), the founding member of the SLC26 sulfate transporter family, mediates sulfate exit across the basolateral membrane to complete the process of transtubular sulfate reabsorption. Another member of this family, CFEX (SLC26A6), is present at the apical membrane of proximal tubular cells. It also can transport sulfate by anion exchange, which probably mediates backflux of sulfate into the lumen. Knockout mouse studies have demonstrated a major role of CFEX as an apical membrane Cl(-)/oxalate exchanger that contributes to NaCl reabsorption in the proximal tubule. Several additional SLC26 family members mediate sulfate transport and show some level of renal expression (e.g., SLC26A2, SLC26A7, SLC26A11). Their roles in mediating renal tubular sulfate transport are presently unknown. This paper reviews current data available on the function and regulation of three sulfate transporters (NaS1, SAT1, and CFEX) and their physiological roles in the kidney.
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http://dx.doi.org/10.1146/annurev.physiol.69.040705.141319DOI Listing
April 2007