scholarly journals Oxalate: From the Environment to Kidney Stones

2013 ◽  
Vol 64 (4) ◽  
pp. 609-630 ◽  
Author(s):  
Hrvoje Brzica ◽  
Davorka Breljak ◽  
Birgitta C Burckhardt ◽  
Gerhard Burckhardt ◽  
Ivan Sabolić
Keyword(s):  
Underlying Mechanism ◽  
Stone Disease ◽  
Sulfate Anion ◽  
Intestinal Excretion ◽  
Oxalate Absorption ◽  
Anion Transporter ◽  
Solute Carrier ◽  
Sat 1 ◽  
Oxalate Transport

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.

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

2008 ◽  
Vol 457 (6) ◽  
pp. 1381-1392 ◽  
Author(s):  
Hrvoje Brzica ◽  
Davorka Breljak ◽  
Wolfgang Krick ◽  
Mila Lovrić ◽  
Gerhard Burckhardt ◽  
...  
Keyword(s):  
Gender Differences ◽  
Sulfate Anion ◽  
Anion Transporter ◽  
Liver And Kidney ◽  
Sat 1

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

2009 ◽  
Vol 297 (1) ◽  
pp. F145-F154 ◽  
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.

scholarly journals Sat1 is dispensable for active oxalate secretion in mouse duodenum

2012 ◽  
Vol 303 (1) ◽  
pp. C52-C57 ◽  
Author(s):  
Narae Ko ◽  
Felix Knauf ◽  
Zhirong Jiang ◽  
Daniel Markovich ◽  
Peter S. Aronson
Keyword(s):  
Calcium Oxalate ◽  
Basolateral Membrane ◽  
Complete Removal ◽  
Calcium Oxalate Stones ◽  
Anion Transporter ◽  
Oxalate Secretion ◽  
In Series ◽  
Disulfonic Stilbene ◽  
Oxalate Transport

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.

scholarly journals Physiological roles of renal anion transporters NaS1 and Sat1

2011 ◽  
Vol 300 (6) ◽  
pp. F1267-F1270 ◽  
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.

Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6 null mice

2006 ◽  
Vol 290 (4) ◽  
pp. G719-G728 ◽  
Author(s):  
Robert W. Freel ◽  
Marguerite Hatch ◽  
Mike Green ◽  
Manoocher Soleimani
Keyword(s):  
Apical Membrane ◽  
Urinary Oxalate ◽  
Calcium Oxalate Stone ◽  
Oxalate Excretion ◽  
Oxalate Absorption ◽  
Anion Transporter ◽  
Urinary Oxalate Excretion ◽  
Net Fluxes ◽  
Oxalate Transport ◽  
Mouse Ileum

Intestinal oxalate transport, mediated by anion exchange proteins, is important to oxalate homeostasis and consequently to calcium oxalate stone diseases. To assess the contribution of the putative anion transporter (PAT)1 (Slc26a6) to transepithelial oxalate transport, we compared the unidirectional and net fluxes of oxalate across isolated, short-circuited segments of the distal ileum of wild-type (WT) mice and Slc26a6 null mice [knockout (KO)]. Additionally, urinary oxalate excretion was measured in both groups. In WT mouse ileum, there was a small net secretion of oxalate ([Formula: see text]), whereas in KO mice JnetOxwas significantly absorptive (75 ± 10 pmol·cm−2h·h−1), which was the result of a smaller serosal-to-mucosal oxalate flux ( JsmOx) and a larger mucosal-to-serosal oxalate flux ( JmsOx). Mucosal DIDS (200 μM) reduced JsmOxin WT mice, leading to reversal of the direction of net oxalate transport from secretion to absorption ([Formula: see text]) , but DIDS had no significant effect on KO ileum. In WT mice in the absence of mucosal Cl−, there were small increases in JmsOxand decreases in JsmOxthat led to a small net oxalate absorption. In KO mice, JnetOxwas 1.5-fold greater in the absence of mucosal Cl−, due solely to an increase in JmsOx. Urinary oxalate excretion was about fourfold greater in KO mice compared with WT littermates. We conclude that PAT1 is DIDS sensitive and mediates a significant fraction of oxalate efflux across the apical membrane in exchange for Cl−; as such, PAT1 represents a major apical membrane pathway mediating JsmOx.

Localization of the sulfate/anion exchanger in the rat liver

2006 ◽  
Vol 290 (5) ◽  
pp. G1075-G1081 ◽  
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.

scholarly journals Physiological and Pathological Functions of SLC26A6

2021 ◽  
Vol 7 ◽  
Author(s):  
Juan Wang ◽  
Wenkang Wang ◽  
Hui Wang ◽  
Biguang Tuo
Keyword(s):  
Ion Homeostasis ◽  
Acid Base Balance ◽  
Acid Base ◽  
The Past ◽  
Anion Transporter ◽  
Transporter Family ◽  
Base Balance ◽  
Extensive Exchange ◽  
Solute Carrier

Solute Carrier Family 26 (SLC26) is a conserved anion transporter family with 10 members in human (SLC26A1-A11, A10 being a pseudogene). All SLC26 genes except for SLC26A5 (prestin) are versatile anion exchangers with notable ability to transport a variety of anions. SLC26A6 has the most extensive exchange functions in the SLC26 family and is widely expressed in various organs and tissues of mammals. SLC26A6 has some special properties that make it play a particularly important role in ion homeostasis and acid-base balance. In the past few years, the function of SLC26A6 in the diseases has received increasing attention. SLC26A6 not only participates in the development of intestinal and pancreatic diseases but also serves a significant role in mediating nephrolithiasis, fetal skeletal dysplasia and arrhythmia. This review aims to explore the role of SLC26A6 in physiology and pathophysiology of relative mammalian organs to guide in-depth studies about related diseases of human.

scholarly journals Kindlin-2 mediates mechanotransduction in bone by regulating expression of Sclerostin in osteocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Lei Qin ◽  
Xuekun Fu ◽  
Jing Ma ◽  
Manxia Lin ◽  
Peijun Zhang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Mechanical Stimulation ◽  
Fluid Shear Stress ◽  
Weight Bearing ◽  
Underlying Mechanism ◽  
Long Bones ◽  
Cell Orientation ◽  
Cytoskeleton Organization

AbstractOsteocytes act as mechanosensors in bone; however, the underlying mechanism remains poorly understood. Here we report that deleting Kindlin-2 in osteocytes causes severe osteopenia and mechanical property defects in weight-bearing long bones, but not in non-weight-bearing calvariae. Kindlin-2 loss in osteocytes impairs skeletal responses to mechanical stimulation in long bones. Control and cKO mice display similar bone loss induced by unloading. However, unlike control mice, cKO mice fail to restore lost bone after reloading. Osteocyte Kindlin-2 deletion impairs focal adhesion (FA) formation, cytoskeleton organization and cell orientation in vitro and in bone. Fluid shear stress dose-dependently increases Kindlin-2 expression and decreases that of Sclerostin by downregulating Smad2/3 in osteocytes; this latter response is abolished by Kindlin-2 ablation. Kindlin-2-deficient osteocytes express abundant Sclerostin, contributing to bone loss in cKO mice. Collectively, we demonstrate an indispensable novel role of Kindlin-2 in maintaining skeletal responses to mechanical stimulation by inhibiting Sclerostin expression during osteocyte mechanotransduction.

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