The liver and kidney expression of sulfate anion transporter sat-1 in rats exhibits male-dominant gender differences

Abstract Oxalate urolithiasis (nephrolithiasis) is the most frequent type of kidney stone disease. Epidemiological research has shown that urolithiasis is approximately twice as common in men as in women, but the underlying mechanism of this sex-related prevalence is unclear. Oxalate in the organism partially originate from food (exogenous oxalate) and largely as a metabolic end-product from numerous precursors generated mainly in the liver (endogenous oxalate). Oxalate concentrations in plasma and urine can be modified by various foodstuffs, which can interact in positively or negatively by affecting oxalate absorption, excretion, and/or its metabolic pathways. Oxalate is mostly removed from blood by kidneys and partially via bile and intestinal excretion. In the kidneys, after reaching certain conditions, such as high tubular concentration and damaged integrity of the tubule epithelium, oxalate can precipitate and initiate the formation of stones. Recent studies have indicated the importance of the SoLute Carrier 26 (SLC26) family of membrane transporters for handling oxalate. Two members of this family [Sulfate Anion Transporter 1 (SAT-1; SLC26A1) and Chloride/Formate EXchanger (CFEX; SLC26A6)] may contribute to oxalate transport in the intestine, liver, and kidneys. Malfunction or absence of SAT-1 or CFEX has been associated with hyperoxaluria and urolithiasis. However, numerous questions regarding their roles in oxalate transport in the respective organs and male-prevalent urolithiasis, as well as the role of sex hormones in the expression of these transporters at the level of mRNA and protein, still remain to be answered.

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Localization of the sulfate/anion exchanger in the rat liver

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00492.2005 ◽

2006 ◽

Vol 290 (5) ◽

pp. G1075-G1081 ◽

Cited By ~ 16

Author(s):

Fabio Quondamatteo ◽

Wolfgang Krick ◽

Yohannes Hagos ◽

Marie-Helen Krüger ◽

Katrin Neubauer-Saile ◽

...

Keyword(s):

Endothelial Cells ◽

Rat Liver ◽

Isolated Hepatocytes ◽

Proteoglycan Synthesis ◽

Expression Cloning ◽

Sulfate Uptake ◽

Sulfate Anion ◽

Estrone Sulfate ◽

Anion Transporter ◽

Sat 1

Although the sulfate/anion transporter (sat-1; SLC26A1) was isolated from a rat liver cDNA library by expression cloning, localization of sat-1 within the liver and its contribution to the transport of sulfate and organo sulfates have remained unresolved. In situ hybridization and immunohistochemical studies were undertaken to demonstrate the localization of sat-1 in liver tissue. RT-PCR studies on isolated hepatocytes and liver endothelial and stellate cells in culture were performed to test for the presence of sat-1 in these cells. In sulfate uptake and efflux experiments, the substrate specificity of sat-1 was evaluated. Sat-1 mRNA was found in hepatocytes and endothelial cells. Sat-1 protein was localized in sinusoidal membranes and along the borders of hepatocytes. The canalicular region and bile capillaries were not stained. Sulfate uptake was only slightly affected by sulfamoyl diuretics or organo sulfates. Sulfate efflux from sat-1-expressing oocytes was enhanced in the presence of bicarbonate, indicating sulfate/bicarbonate exchange. Estrone sulfate was not transported by sat-1. Sat-1 may be responsible for the uptake of inorganic sulfate from the blood into hepatocytes to enable sulfation reactions. In hepatocytes and endothelial cells, sat-1 may also supply sulfate for proteoglycan synthesis.

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Renal expression of organic anion transporter OAT2 in rats and mice is regulated by sex hormones

AJP Renal Physiology ◽

10.1152/ajprenal.00207.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. F361-F372 ◽

Cited By ~ 59

Author(s):

Marija Ljubojević ◽

Daniela Balen ◽

Davorka Breljak ◽

Marija Kušan ◽

Naohiko Anzai ◽

...

Keyword(s):

Gender Differences ◽

Mrna Expression ◽

Rat Kidney ◽

Organic Anion ◽

Staining Intensity ◽

Protein Band ◽

Organic Anion Transporter ◽

Adult Rats ◽

Anion Transporters ◽

Anion Transporter

The renal reabsorption and/or excretion of various organic anions is mediated by specific organic anion transporters (OATs). OAT2 (Slc22a7) has been identified in rat kidney, where its mRNA expression exhibits gender differences [females (F) > males (M)]. The exact localization of OAT2 protein in the mammalian kidney has not been reported. Here we studied the expression of OAT2 mRNA by RT-PCR and its protein by Western blotting (WB) and immunocytochemistry (IC) in kidneys of adult intact and gonadectomized M and F, sex hormone-treated castrated M, and prepubertal M and F rats, and the protein in adult M and F mice. In adult rats, the expression of OAT2 mRNA was predominant in the outer stripe (OS) tissue, exhibiting 1) gender dependency (F > M), 2) upregulation by castration and downregulation by ovariectomy, and 3) strong downregulation by testosterone and weak upregulation by estradiol and progesterone treatment. A polyclonal antibody against rat OAT2 on WB of isolated renal membranes labeled a ∼66-kDa protein band that was stronger in F. By IC, the antibody exclusively stained brush border (BB) of the proximal tubule S3 segment (S3) in the OS and medullary rays (F > M). In variously treated rats, the pattern of 66-kDa band density in the OS membranes and the staining intensity of BB in S3 matched the mRNA expression. The expression of OAT2 protein in prepubertal rats was low and gender independent. In mice, the expression pattern largely resembled that in rats. Therefore, OAT2 in rat (and mouse) kidney is localized to the BB of S3, exhibiting gender differences (F > M) that appear in puberty and are caused by strong androgen inhibition and weak estrogen and progesterone stimulation.

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Identification of a Novel Organic Anion Transporter Mediating Carnitine Transport in Mouse Liver and Kidney

Cellular Physiology and Biochemistry ◽

10.1159/000303060 ◽

2010 ◽

Vol 25 (4-5) ◽

pp. 511-522 ◽

Cited By ~ 18

Author(s):

Hiroki Tsuchida ◽

Naohiko Anzai ◽

Ho Shin ◽

Michael Wempe ◽

Promsuk Jutabha ◽

...

Keyword(s):

Mouse Liver ◽

Organic Anion ◽

Organic Anion Transporter ◽

Anion Transporter ◽

Carnitine Transport ◽

Liver And Kidney

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Ability of sat-1 to transport sulfate, bicarbonate, or oxalate under physiological conditions

AJP Renal Physiology ◽

10.1152/ajprenal.90401.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. F145-F154 ◽

Cited By ~ 22

Author(s):

Wolfgang Krick ◽

Nina Schnedler ◽

Gerhard Burckhardt ◽

Birgitta C. Burckhardt

Keyword(s):

Basolateral Membrane ◽

Physiological Role ◽

Experimental Conditions ◽

Simultaneous Application ◽

Proximal Tubule Cells ◽

Sulfate Anion ◽

Electrode Voltage ◽

Electrophysiological Studies ◽

Sat 1

Tubular reabsorption of sulfate is achieved by the sodium-dependent sulfate transporter, NaSi-1, located at the apical membrane, and the sulfate-anion exchanger, sat-1, located at the basolateral membrane. To delineate the physiological role of rat sat-1, [35S]sulfate and [14C]oxalate uptake into sat-1-expressing oocytes was determined under various experimental conditions. Influx of [35S]sulfate was inhibited by bicarbonate, thiosulfate, sulfite, and oxalate, but not by sulfamate and sulfide, in a competitive manner with Ki values of 2.7 ± 1.3 mM, 101.7 ± 9.7 μM, 53.8 ± 10.9 μM, and 63.5 ± 38.7 μM, respectively. Vice versa, [14C]oxalate uptake was inhibited by sulfate with a Ki of 85.9 ± 9.5 μM. The competitive type of inhibition indicates that these compounds are most likely substrates of sat-1. Physiological plasma bicarbonate concentrations (25 mM) reduced sulfate and oxalate uptake by more than 75%. Simultaneous application of sulfate, bicarbonate, and oxalate abolished sulfate as well as oxalate uptake. These data and electrophysiological studies using a two-electrode voltage-clamp device provide evidence that sat-1 preferentially works as an electroneutral sulfate-bicarbonate or oxalate-bicarbonate exchanger. In kidney proximal tubule cells, sat-1 likely completes sulfate reabsorption from the ultrafiltrate across the basolateral membrane in exchange for bicarbonate. In hepatocytes, oxalate extrusion is most probably mediated either by an exchange for sulfate or bicarbonate.

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Absence of the sulfate transporter SAT-1 has no impact on oxalate handling by mouse intestine and does not cause hyperoxaluria or hyperoxalemia

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00299.2018 ◽

2019 ◽

Vol 316 (1) ◽

pp. G82-G94 ◽

Cited By ~ 5

Author(s):

Jonathan M. Whittamore ◽

Christine E. Stephens ◽

Marguerite Hatch

Keyword(s):

Calcium Oxalate ◽

Stone Formation ◽

Distal Colon ◽

Toxic Waste ◽

Oxalate Excretion ◽

Anion Transporter ◽

Oxalate Secretion ◽

Mechanistic Basis ◽

Urinary Oxalate Excretion ◽

Sat 1

The anion exchanger SAT-1 [sulfate anion transporter 1 (Slc26a1)] is considered an important regulator of oxalate and sulfate homeostasis, but the mechanistic basis of these critical roles remain undetermined. Previously, characterization of the SAT-1-knockout (KO) mouse suggested that the loss of SAT-1-mediated oxalate secretion by the intestine was responsible for the hyperoxaluria, hyperoxalemia, and calcium oxalate urolithiasis reportedly displayed by this model. To test this hypothesis, we compared the transepithelial fluxes of 14C-oxalate, 35[Formula: see text], and 36Cl− across isolated, short-circuited segments of the distal ileum, cecum, and distal colon from wild-type (WT) and SAT-1-KO mice. The absence of SAT-1 did not impact the transport of these anions by any part of the intestine examined. Additionally, SAT-1-KO mice were neither hyperoxaluric nor hyperoxalemic. Instead, 24-h urinary oxalate excretion was almost 50% lower than in WT mice. With no contribution from the intestine, we suggest that this may reflect the loss of SAT-1-mediated oxalate efflux from the liver. SAT-1-KO mice were, however, profoundly hyposulfatemic, even though there were no changes to intestinal sulfate handling, and the renal clearances of sulfate and creatinine indicated diminished rates of sulfate reabsorption by the proximal tubule. Aside from this distinct sulfate phenotype, we were unable to reproduce the hyperoxaluria, hyperoxalemia, and urolithiasis of the original SAT-1-KO model. In conclusion, oxalate and sulfate transport by the intestine were not dependent on SAT-1, and we found no evidence supporting the long-standing hypothesis that intestinal SAT-1 contributes to oxalate and sulfate homeostasis. NEW & NOTEWORTHY SAT-1 is a membrane-bound transport protein expressed in the intestine, liver, and kidney, where it is widely considered essential for the excretion of oxalate, a potentially toxic waste metabolite. Previously, calcium oxalate kidney stone formation by the SAT-1-knockout mouse generated the hypothesis that SAT-1 has a major role in oxalate excretion via the intestine. We definitively tested this proposal and found no evidence for SAT-1 as an intestinal anion transporter contributing to oxalate homeostasis.

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Physiological roles of renal anion transporters NaS1 and Sat1

AJP Renal Physiology ◽

10.1152/ajprenal.00061.2011 ◽

2011 ◽

Vol 300 (6) ◽

pp. F1267-F1270 ◽

Cited By ~ 8

Author(s):

Daniel Markovich

Keyword(s):

Current Knowledge ◽

Targeted Disruption ◽

Sulfate Anion ◽

Calcium Oxalate Urolithiasis ◽

Anion Transporters ◽

Anion Transporter ◽

Proximal Tubular ◽

Renal Proximal Tubular ◽

Oxalate Transport

This review will briefly summarize current knowledge on the renal anion transporters sodium-sulfate cotransporter-1 (NaS1; Slc13a1) and sulfate-anion transporter-1 (Sat1; Slc26a1). NaS1 and Sat1 mediate renal proximal tubular sulfate reabsorption and thereby regulate blood sulfate levels. Sat1 also mediates renal oxalate transport and controls blood oxalate levels. Targeted disruption of murine NaS1 and Sat1 leads to hyposulfatemia and hypersulfaturia. Sat1 null mice also exhibit hyperoxalemia, hyperoxaluria, and calcium oxalate urolithiasis. NaS1 and Sat1 null mice also have other phenotypes that result due to changes in blood sulfate and oxalate levels. Experimental data indicate that NaS1 is essential for maintaining sulfate homeostasis, whereas Sat1 controls both sulfate and oxalate homeostasis in vivo.

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