Oxalate Transport Research Articles

Effects of acid-base variables and the role of carbonic anhydrase on oxalate secretion by the mouse intestine in vitro.

Hyperoxaluria is a major risk factor for calcium oxalate kidney stones and the intestine is recognized as an important extra-renal pathway for eliminating oxalate. The membrane-bound chloride/bicarbonate (Cl−/) exchangers are involved in the transcellular movement of oxalate, but little is understood about how they might be regulated. , CO2, and pH are established modulators of intestinal NaCl cotransport, involving Na+/H+ and Cl−/ exchange, but their influence on oxalate transport is unknown. Measuring 14C-oxalate and 36Cl fluxes across isolated, short-circuited segments of the mouse distal ileum and distal colon we examined the role of these acid-base variables and carbonic anhydrase (CA) in oxalate and Cl− transport. In standard buffer both segments performed net oxalate secretion (and Cl− absorption), but only the colon, and the secretory pathway were responsive to and CO2. Ethoxzolamide abolished net oxalate secretion by the distal colon, and when used in tandem with an impermeant CA inhibitor, signaled an intracellular CA isozyme was required for secretion. There was a clear dependence on as their removal eliminated secretion, while at 42 mmol/L was also decreased and eradicated. Independent of pH, raising Pco2 from 28 to 64 mmHg acutely stimulated net oxalate secretion 41%. In summary, oxalate secretion by the distal colon was dependent on , CA and specifically modulated by CO2, whereas the ileum was remarkably unresponsive. These findings highlight the distinct segmental heterogeneity along the intestine, providing new insights into the oxalate transport mechanism and how it might be regulated.

Physiological Implications of Transepithelial Carboxylic Acid Absorption and Regulation by Slc26a6

The combination of increased urinary oxalate and attenuated urinary citrate concentration are a major risk factor for Ca2+-oxalate kidney stone formation, even when urinary Ca2+ levels are not elevated. Nevertheless, the molecular mechanisms that regulate urinary oxalate and citrate levels are not well understood. We studied the role of the oxalate transporter, slc26a6, and the citrate transporter, NaDC-1, in regulating oxalate/citrate homeostasis. We found that Slc26a6-null mice exhibited increased renal and intestinal sodium-dependent succinate uptake which is attributed to NaDC-1 function. Furthermore, we monitored urinary hyperoxaluria and hypocitraturia, but no change in urinary pH, indicating enhanced transport activity of NaDC-1 in slc26a6-null mice. When co-expressed in xenopus oocytes, Slc26a6 dramatically inhibited NaDC-1 transport activity in an activity dependent manner. Finally, biochemical and physiological analysis revealed that the STAS domain of Slc26a6 and the first intracellular loop of NaDC-1 mediated both the physical and functional interactions of these transporters. Our findings reveal a molecular pathway that tightly regulates oxalate and citrate concentration and may control biological Ca2+-oxalate stone formation in the kidney and other organs like, for example, salivary glands.

Binding abilities of copper to phospholipids and transport of oxalate

Cu(II) creates complexes with dipalmitoylphosphatidylcholine (lecithin), which are detectable using electrospray ionization mass spectrometry. Lecithin (L) as a relatively big ligand prevents Cu(II) reduction to Cu(I) during the electrospray process. The detected complexes include (1) dications with a general formula: [Cu(L) n ]2+, where n prevails from 2 to 5 (in the m/z range from 50 to 2,000); and (2) monocations originated from the metal salt precursor [CuCl(L) k ]+ (k is 1 or 2). The Cu(II)/lecithin complexes are stable enough (appearance energy higher than 200 kJ mol−1) to utilize Cu(II) for stabilization of an artificial membrane. The impermeability of an artificial phospholipid membrane for oxalic acid and its complexes with copper ions in slightly acidic pH 5 was confirmed voltammetrically. However, adsorption of copper–oxalate complexes on the membrane surface was proved using electrochemical impedance spectroscopy. .

The Structure and Function of OxlT, the Oxalate Transporter of Oxalobacter formigenes.

OxlT, the oxalate transporter of Oxalobacter formigenes, is a member of the Major Facilitator Superfamily of transporters (MFS), one of the largest groups of membrane proteins with substantial relevance to solute transport physiology, pharmacology, and possible drug development. MFS proteins transport a wide range of substrates such as organic and inorganic anions, sugars, drugs, and neurotransmitters. This review succinctly summarizes experimental work on a model MFS protein, OxlT, beginning with its identification as an electrogenic oxalate/formate exchanger, its three-dimensional structure, and discussion of biochemical and biophysical data that have shed further light on its structure and function. We also discuss the structure and function of OxlT in relation to notable MFS carriers such as LacY and GlpT.

Intestinal adaptations in chronic kidney disease and the influence of gastric bypass surgery.

Studies have shown that compensatory adaptations in gastrointestinal oxalate transport can impact the amount of oxalate excreted by the kidney. Hyperoxaluria is a major risk factor in the formation of kidney stones, and oxalate is derived from both the diet and the liver metabolism of glyoxylate. Although the intestine generally absorbs oxalate from dietary sources and can contribute as much as 50% of urinary oxalate, enteric oxalate elimination plays a significant role when renal function is compromised. While the mechanistic basis for these changes in the direction of intestinal oxalate movements in chronic renal failure involves an upregulation of angiotensinII receptors in the large intestine, enteric secretion/excretion of oxalate can also occur by mechanisms that are independent of angiotensinII. Most notably, the commensal bacterium Oxalobacter sp. interacts with the host enterocyte and promotes the movement of oxalate from the blood into the lumen, resulting in the beneficial effect of significantly lowering urinary oxalate excretion. Changes in the passive permeability of the intestine, such as in steatorrhoea and following gastric bypass, also promote oxalate absorption and hyperoxaluria. In summary, this report highlights the two-way physiological signalling between the gut and the kidney, which may help to alleviate the consequences of certain kidney diseases.

Pseudomonas fluorescens ATCC 13525 Containing an Artificial Oxalate Operon and Vitreoscilla Hemoglobin Secretes Oxalic Acid and Solubilizes Rock Phosphate in Acidic Alfisols

Oxalate secretion was achieved in Pseudomonas fluorescens ATCC 13525 by incorporation of genes encoding Aspergillus niger oxaloacetate acetyl hydrolase (oah), Fomitopsis plaustris oxalate transporter (FpOAR) and Vitreoscilla hemoglobin (vgb) in various combinations. Pf (pKCN2) transformant containing oah alone accumulated 19 mM oxalic acid intracellularly but secreted 1.2 mM. However, in the presence of an artificial oxalate operon containing oah and FpOAR genes in plasmid pKCN4, Pf (pKCN4) secreted 13.6 mM oxalate in the medium while 3.6 mM remained inside. This transformant solubilized 509 μM of phosphorus from rock phosphate in alfisol which is 4.5 fold higher than the Pf (pKCN2) transformant. Genomic integrants of P. fluorescens (Pf int1 and Pf int2) containing artificial oxalate operon (plac-FpOAR-oah) and artificial oxalate gene cluster (plac-FpOAR-oah, vgb, egfp) secreted 4.8 mM and 5.4 mM oxalic acid, released 329 μM and 351 μM P, respectively, in alfisol. The integrants showed enhanced root colonization, improved growth and increased P content of Vigna radiata plants. This study demonstrates oxalic acid secretion in P. fluorescens by incorporation of an artificial operon constituted of genes for oxalate synthesis and transport, which imparts mineral phosphate solubilizing ability to the organism leading to enhanced growth and P content of V. radiata in alfisol soil.

Acid‐base regulation of intestinal oxalate transport (LB716)

Primary Hyperoxaluria (PH) is a rare, inherited disease caused by an absence of specific liver enzyme(s) leading to overproduction of oxalate (Ox2‐), kidney stones and eventual renal failure. Alongside the kidney, the intestine is capable of secreting Ox2‐ and reducing the systemic Ox2‐ burden. Preserving renal function in PH is paramount therefore the notion of extra‐renal Ox2‐ elimination should not be under‐estimated. Identification of chloride/bicarbonate (Cl‐/HCO3‐) exchangers with an affinity for Ox2‐ raises the possibility of these membrane‐bound proteins serving as future therapeutic targets for promoting Ox2‐ secretion in PH. Despite this interest, understanding how these transporters are regulated is not well defined. Components of the HCO3‐‐buffering system (pH, CO2 and HCO3‐) are important, but under‐appreciated regulators of Cl‐/HCO3‐ exchange. The objective of this study was to determine whether these acid‐base variables, and associated enzyme, carbonic anhydrase (CA), are involved in Ox2‐ handling. Isolated mouse intestinal preparations were mounted in an Ussing chamber and experiments systematically examined how changes to pH, PCO2 and [HCO3‐] impacted Ox2‐ fluxes. Results showed that Ox2‐ secretion by the distal colon requires CA activity, is sensitive to changing [HCO3‐], but not pH, and can be stimulated > 70 % by increasing PCO2. In contrast, Ox2‐ transport by the ileum was impervious to these maneuvers. This sets the foundation for more detailed studies into the identity of the transporter(s) responsible, the role of CA, and the underlying signaling pathway. These findings also highlight the heterogeneity of intestinal Ox2‐ handling, being regulated by distinct stimuli in different segments that express a similar suite of Cl‐/HCO3‐ exchangers.Grant Funding Source: Supported by a Career Development Fellowship from the Rare Kidney Stone Consortium at the Mayo Clinic, Rochester, MN (NIH 5U54 DK083908‐05)

Oxalate: From the Environment to Kidney Stones

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.

A human strain of Oxalobacter (HC-1) promotes enteric oxalate secretion in the small intestine of mice and reduces urinary oxalate excretion

Enteric oxalate secretion that correlated with reductions in urinary oxalate excretion was previously reported in a mouse model of primary hyperoxaluria, and in wild type (WT) mice colonized with a wild rat strain (OXWR) of Oxalobacter (Am J Physiol 300:G461–G469, 2010). Since a human strain of the bacterium is more likely to be clinically used as a probiotic therapeutic, we tested the effects of HC-1 in WT. Following artificial colonization of WT mice with HC-1, the bacteria were confirmed to be present in the large intestine and, unexpectedly, detected in the small intestine for varying periods of time. The main objective of the present study was to determine whether the presence of HC-1 promoted intestinal secretion in the more proximal segments of the gastrointestinal tract. In addition, we determined whether HC-1 colonization led to reductions in urinary oxalate excretion in these mice. The results show that the human Oxalobacter strain promotes a robust net secretion of oxalate in the distal ileum as well as in the caecum and distal colon and these changes in transport correlate with the beneficial effect of reducing renal excretion of oxalate. We conclude that OXWR effects on intestinal oxalate transport and oxalate homeostasis are not unique to the wild rat strain and that, mechanistically, HC-1 has significant potential for use as a probiotic treatment for hyperoxaluria especially if it is also targeted to the upper and lower gastrointestinal tract.

Transcellular oxalate and Cl−absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate

Active transcellular oxalate transport in the mammalian intestine contributes to the homeostasis of this important lithogenic anion. Several members of the Slc26a gene family of anion exchangers have a measurable oxalate affinity and are expressed along the gut, apically and basolaterally. Mouse Slc26a6 (PAT1) targets to the apical membrane of enterocytes in the small intestine, and its deletion results in net oxalate absorption and hyperoxaluria. Apical exchangers of the Slc26a family that mediate oxalate absorption have not been established, yet the Slc26a3 [downregulated in adenoma (DRA)] protein is a candidate mediator of oxalate uptake. We evaluated the role of DRA in intestinal oxalate and Cl(-) transport by comparing unidirectional and net ion fluxes across short-circuited segments of small (ileum) and large (cecum and distal colon) intestine from wild-type (WT) and DRA knockout (KO) mice. In WT mice, all segments demonstrated net oxalate and Cl(-) absorption to varying degrees. In KO mice, however, all segments exhibited net anion secretion, which was consistently, and solely, due to a significant reduction in the absorptive unidirectional fluxes. In KO mice, daily urinary oxalate excretion was reduced 66% compared with that in WT mice, while urinary creatinine excretion was unchanged. We conclude that DRA mediates a predominance of the apical uptake of oxalate and Cl(-) absorbed in the small and large intestine of mice under short-circuit conditions. The large reductions in urinary oxalate excretion underscore the importance of transcellular intestinal oxalate absorption, in general, and, more specifically, the importance of the DRA exchanger in oxalate homeostasis.

SLC26A6 and NaDC-1 Transporters Interact to Regulate Oxalate and Citrate Homeostasis

The combination of hyperoxaluria and hypocitraturia can trigger Ca(2+)-oxalate stone formation, even in the absence of hypercalciuria, but the molecular mechanisms that control urinary oxalate and citrate levels are not understood completely. Here, we examined the relationship between the oxalate transporter SLC26A6 and the citrate transporter NaDC-1 in citrate and oxalate homeostasis. Compared with wild-type mice, Slc26a6-null mice exhibited increased renal and intestinal sodium-dependent succinate uptake, as well as urinary hyperoxaluria and hypocitraturia, but no change in urinary pH, indicating enhanced transport activity of NaDC-1. When co-expressed in Xenopus oocytes, NaDC-1 enhanced Slc26a6 transport activity. In contrast, Slc26a6 inhibited NaDC-1 transport activity in an activity dependent manner to restricted tubular citrate absorption. Biochemical and physiologic analysis revealed that the STAS domain of Slc26a6 and the first intracellular loop of NaDC-1 mediated both the physical and functional interactions of these transporters. These findings reveal a molecular pathway that senses and tightly regulates oxalate and citrate levels and may control Ca(2+)-oxalate stone formation.

Extracellular nucleotides inhibit oxalate transport by human intestinal Caco-2-BBe cells through PKC-δ activation

Nephrolithiasis remains a major health problem in Western countries. Seventy to 80% of kidney stones are composed of calcium oxalate, and small changes in urinary oxalate affect risk of kidney stone formation. Intestinal oxalate secretion mediated by the anion exchanger SLC26A6 plays an essential role in preventing hyperoxaluria and calcium oxalate nephrolithiasis, indicating that understanding the mechanisms regulating intestinal oxalate transport is critical for management of hyperoxaluria. Purinergic signaling modulates several intestinal processes through pathways including PKC activation, which we previously found to inhibit Slc26a6 activity in mouse duodenal tissue. We therefore examined whether purinergic stimulation with ATP and UTP affects oxalate transport by human intestinal Caco-2-BBe (C2) cells. We measured [¹⁴C]oxalate uptake in the presence of an outward Cl⁻ gradient as an assay of Cl⁻/oxalate exchange activity, ≥50% of which is mediated by SLC26A6. We found that ATP and UTP significantly inhibited oxalate transport by C2 cells, an effect blocked by the PKC inhibitor Gö-6983. Utilizing pharmacological agonists and antagonists, as well as PKC-δ knockdown studies, we observed that ATP inhibits oxalate transport through the P2Y₂ receptor, PLC, and PKC-δ. Biotinylation studies showed that ATP inhibits oxalate transport by lowering SLC26A6 surface expression. These findings are of potential relevance to pathophysiology of inflammatory bowel disease-associated hyperoxaluria, where supraphysiological levels of ATP/UTP are expected and overexpression of the P2Y₂ receptor has been reported. We conclude that ATP and UTP inhibit oxalate transport by lowering SLC26A6 surface expression in C2 cells through signaling pathways including the P2Y₂ purinergic receptor, PLC, and PKC-δ.

Using Drosophila to identify inhibitors of oxalate kidney stone formation

BackgroundKidney stones are an expensive and painful health problem with calcium oxalate (CaOx) being 70% of cases. We developed a Drosophila model of CaOx stones [Hirata et al., AJP‐Renal Physiol, 2012]. This work showed that dPrestin (Slc26a5/a6) exchanges Cl− for oxalate (Ox). Thiosulfate (S2O3) and tannic acid (TA) are implicated to inhibit CaOx crystals in supersaturated urine. Here, we report transporter, renal tubule and whole body effects of S2O3 and TA on crystal formation.MethodsS2O3 and TA transport effects were examined by voltage clamping of dPrestin‐expressing Xenopus oocytes. Cis‐inhibition of oxalate transport was also examined in (a) dissected Malpighian tubules (MT) or flies fed ox‐enriched food plus S2O3 or TA. MT CaOx crystals were viewed by DIC, or whole flies by microCT.ResultsdPrestin transports S2O3 but not TA, yet both inhibited Ox transport (Ki(S2O3)~10mM; Ki(TA)~100μM). S2O3 competitively inhibits while TA blocks dPrestin. MT treated with S2O3 or TA ↓ crystal formation compared to MT soaked in Ox only. Flies fed with S2O3 or TA also showed ↓ CaOx in MTs.ConclusionsS2O3 and TA are both inhibitors of CaOx crystallization. These experiments show that these inhibitors have distinct mechanisms of action. Our Results indicate that (a) this Drosophila model can be used as a chemical screening assay for CaOx stone prevention and (b) TA, due to low Ki, might be a reasonable therapy for certain CaOx stones patients.[DK83007, DK92408]

An Oxalate/Citrate Homeostatic Pathway: The Oxalate Slc26a6 and Citrate NaDC-1 Transporters Interplay

Stone formation is one of the most common urologic diseases in industrialized societies, most prevalent in the kidney and salivary glands. A predominant component of kidney stones is the Ca2+-oxalate crystals found in more than 70% of cases. The stones are formed when renal oxalate and Ca2+ loads increase as a result of their increased level in the filtrate. Stone formation is normally prevented by chelation of urinary Ca2+ by citrate. A change in the oxalate/citrate balance is also required for stone formation. A link between Ca2+-oxalate kidney stones and the oxalate transporter Slc26a6 has been described in Slc26a6-/- mice, where the major phenotype is Ca2+-oxalate stone formation. Nevertheless, the molecular mechanism that maintains oxalate/citrate balance remains unknown. Here, we report in-vivo and in-vitro interplay between the oxalate transporter Slc26a6 and the citrate transporter NaDC-1 to achieve a balanced citrate/oxalate homeostasis. Thus, Slc26a6 markedly inhibits NaDC-1 to limit citrate absorption at increased oxalate loads. At the same time, NaDC-1 activates Slc26a6 to allow oxalate clearance when citrate load is high. The interaction between the oxalate and citrate transporters is mediated by the Slc26a6 STAS domain and the NaDC-1 first intracellular loop. The STAS domain and the first intracellular loop are sufficient to mediate the reciprocal regulation. Accordingly, deletion of Slc26a6 in mice enhanced the activity of the native NaDC-1. These findings reveal a molecular pathway that senses and tightly regulates renal oxalate and citrate that likely function in other organs, such as the salivary glands, to guard against Ca2+-oxalate stone formation.

Substitution of transmembrane domain Cys residues alters pHo-sensitive anion transport by AE2/SLC4A2 anion exchanger

AE2/SLC4A2 is the most widely expressed of the Na(+)-independent SLC4 Cl(-)/HCO3 (-) exchangers and is essential for postnatal survival, but its structure remains unknown. We have generated and expressed a mouse AE2 construct devoid of transmembrane domain cysteine (Cys) residues, mAE2Cys-less, to enhance the utility of Cys-substitution mutagenesis for structural and structure-function studies of mAE2. mAE2Cys-less expressed in Xenopus oocytes exhibited partial reduction of stilbene disulfonate-sensitive anion exchange activity. This activity was independent of the mAE2 N-terminal cytosolic domain and was accompanied by near-normal surface expression, without change in K 1/2 for extracellular Cl(-). mAE2Cys-less exhibited wildtype activation of anion exchange by hypertonicity and by NH4Cl, and wildtype inhibition of anion exchange by acidic intracellular pH (pHi) in the absence of NH4 (+). However, inhibition of anion exchange by extracellular pH (pHo) exhibited an alkaline shifted pHo(50) value of at least 0.6-0.7 pH units. Although SO4 (2-) transport by mAE2Cys-less resembled wildtype mAE2 in its stimulation by acidic pHo, the absence of transmembrane domain Cys residues abrogated activation of oxalate transport by acidic pHo. The contrasting enhancement of SO4 (2-) transport by alkaline pHo in the mAE1 anion translocation pathway mutant E699Q (Am J Physiol Cell Physiol 295: C302) was phenocopied by the corresponding mutant E1007Q in both AE2 and AE2Cys-less. However, the absence of transmembrane domain Cys residues exacerbated the reduced basal anion transport function exhibited by this and other missense substitutions at AE2 residue E1007. AE2Cys-less will be a valuable experimental tool for structure-function studies of the SLC4 gene family, but its utility for studies of AE2 regulation by extracellular pH must be evaluated in the context of its alkaline-shifted pHo sensitivity, resembling that of AE2 gastric parietal cell variant AE2c1.

In vivoDrosophiliagenetic model for calcium oxalate nephrolithiasis

Nephrolithiasis is a major public health problem with a complex and varied etiology. Most stones are composed of calcium oxalate (CaOx), with dietary excess a risk factor. Because of complexity of mammalian system, the details of stone formation remain to be understood. Here we have developed a nephrolithiasis model using the genetic model Drosophila melanogaster, which has a simple, transparent kidney tubule. Drosophilia reliably develops CaOx stones upon dietary oxalate supplementation, and the nucleation and growth of microliths can be viewed in real time. The Slc26 anion transporter dPrestin (Slc26a5/6) is strongly expressed in Drosophilia kidney, and biophysical analysis shows that it is a potent oxalate transporter. When dPrestin is knocked down by RNAi in fly kidney, formation of microliths is reduced, identifying dPrestin as a key player in oxalate excretion. CaOx stone formation is an ancient conserved process across >400 My of divergent evolution (fly and human), and from this study we can conclude that the fly is a good genetic model of nephrolithiasis.

Hyperoxaluric rats do not exhibit alterations in renal expression patterns of Slc26a1 (SAT1) mRNA or protein

Little is known about oxalate transport in renal epithelia under basal conditions, let alone in hyperoxaluria when the capacity for renal oxalate excretion is increased. Sulfate anion transporter 1 (SAT1, Slc26a1) is considered to be a major basolateral anion-oxalate exchanger in the proximal tubule and we hypothesized its expression may correlate with urinary oxalate excretion. We quantified changes in the renal expression of SAT1 mRNA and protein in two rat models, one with hyperoxaluria (HYP) and one with renal insufficiency (HRF) induced by hyperoxaluria. The hyperoxaluria observed in the HYP group could not simply be ascribed to changes in SAT1 mRNA or protein abundance. However, when hyperoxaluria was accompanied by renal insufficiency, significant reductions in SAT1 mRNA and protein were detected in medullary and papillary tissue. Together, the results indicate that transcriptional modulation of the SAT1 gene is not a significant component of the hyperoxaluria observed in these rat models.

Sat1 is dispensable for active oxalate secretion in mouse duodenum

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.

Anion transporter links to urolithiasis and hepatotoxicity

Urolithiasis and hepatotoxicity are linked to perturbations in oxalate and sulfate homeostasis. Urolithiasis is a common disorder leading to significant health care costs. Drug‐induced liver damage is a major cause of death in patients with acute liver failure. Sat1 (Slc26a1) is an anion transporter that mediates epithelial transport of oxalate and sulfate in the kidney, liver and intestine. Creation of Sat1 null (Sat1−/−) mice revealed the physiological roles of Slc26a1 in vivo. Sat1−/− mice exhibit hyperoxaluria with hyperoxalemia, nephrocalcinosis and calcium oxalate stones in their renal tubules and bladder. Sat1−/− mice also have hypersulfaturia, hyposulfatemia and enhanced liver toxicity when subjected to drugs such as acetaminophen. These data suggest Sat1 regulates both oxalate and sulfate homeostasis and is critical to the development of calcium oxalate urolithiasis and hepatotoxicity.Funding from NHMRC, ARC and CCQ grants.

This, too, shall pass—like a kidney stone: a possible path to prophylaxis of nephrolithiasis? Focus on “Cholinergic signaling inhibits oxalate transport by human intestinal T84 cells”

nephrolithiasis (kidney stones) has a lifetime prevalence in the developed world of ∼5% in females, and up to 12% in males, with recurrence in 50% of cases. Normal human urine is supersaturated with respect to the calcium oxalate ion pair, and roughly two thirds of kidney stones are composed