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PubMed1977

'Enteral' hyperoxaluria. Effect of cholestyramine, calcium, neomycin, and bile acids on intestinal oxalate absorption in man.

The effect of oral administration of cholestyramine, neomycine, calcium, and bile acids on intestinal 14C-oxalate absorption and urinary oxalate excretion was assessed in patients with normal or increased ('enteric' hyperoxaluria) urinary oxalate excretion. Cholestyramine, neomycine and acute administration of chenodeoxycholic acid (2.75 g/24 h) did not affect significantly 14C-oxalate absorption or urinary oxalate excretion. Oral administration of calcium markedly reduced 14C-oxalate absorption (88.2%) and urinary oxalate excretion (46%). Calcium-induced reduction of intestinal oxalate absorption was more pronounced in patients with hyperabsorption of oxalate than in subjects with normal oxalate absorption or excretion. Patients on treatment with high doses of chenodeoxycholic acid (1.5-2.0 g/day) for dissolution of cholesterol gallstones had increased oxalate absorption and excretion, patients on long-term treatment with lower doses of chenodeoxycholic acid (0.75-1.0 g/day) exhibited normal absorption or urinary excretion of oxalate. The results do suggest that calcium and bile acids do play an important role in the pathogenesis of 'enteric' hyperoxaluria. It is suggested that the beneficial therapeutic effect of cholestyramine in hyperoxaluria due to ileal resection is rather caused by its bile acid binding property than by direct binding of oxalate within the intestinal lumen.

Bile Acids and Salts↗
PubMed1997

(D)-penicillamine increases hepatic oxalate production resulting in hyperoxaluria.

PURPOSE: To determine whether (D)-penicillamine is effective in reducing hepatic oxalate production and urinary oxalate excretion. MATERIALS AND METHODS: (D)-Penicillamine was administered orally to rats to determine its effect on urinary oxalate excretion and used in isolated rat hepatocytes to investigate the effect of (D)-penicillamine on oxalate production from glycolate. Studies involving hepatic aminotransferases and hepatocytes isolated from (D)-penicillamine treated rats were used to clarify the discrepancy between the in vitro and in vivo results. RESULTS: In hepatocytes (D)-penicillamine lead to a significant reduction in oxalate production from glycolate. In vivo however. (D)-penicillamine led to a significant increase in urinary oxalate excretion and a decrease in plasma aminotransferase activity. Hepatic aminotransferases are involved in diverting oxalate precursors from oxalate production. In vitro, (D)-penicillamine was shown to inhibit hepatic aminotransferases. Hepatocytes isolated from (D)-penicillamine-treated rats produced significantly more oxalate than controls. CONCLUSIONS: These results indicate that (D)-penicillamine increases hepatic oxalate production and urinary oxalate excretion. (D)-penicillamine therefore has no therapeutic potential for reducing endogenous oxalate production and urinary oxalate excretion. Moreover, in conditions such as Wilson's Disease which is often associated with hypercalcuria, its use may be contraindicated.

Animals↗
PubMed1985

The effect of pyridoxine on oxalate dynamics in three cases of primary hyperoxaluria (with glycollic aciduria).

We have measured glomerular filtration rate (GFR), extracellular fluid volume (ECF), oxalate distribution volume (OxDV), plasma oxalate concentration (POx.), plasma total clearance of oxalate (PCOx.), oxalate metabolic pool size [(OxDV) X (POx.)], renal clearance of oxalate (RCOx.), oxalate excretion, tissue clearance of oxalate (TCOx.) and tissue oxalate accumulation rate [(TOx.A) = (TCOx.) X (POx.)] in three patients with type I primary hyperoxaluria (hyperoxaluria with hyperglycollic aciduria) when they were taking pyridoxine and after discontinuation of the vitamin. Seven days after stopping pyridoxine the plasma oxalate concentration, oxalate metabolic pool size and the urinary excretion of oxalate had all increased between seven- and eight-fold in two of the patients. The third patient showed no changes on stopping pyridoxine. These results support the view that pyridoxine acts by reducing oxalate biosynthesis in some patients with type I primary hyperoxaluria. The possible biochemical basis for this effect is discussed.

Adult↗
PubMed2003

Bioavailability of soluble oxalate from spinach eaten with and without milk products.

Leafy vegetables such as spinach (Spinacia oleracea) are known to contain moderate amounts of soluble and insoluble oxalates. Frozen commercially available spinach in New Zealand contains 736.6+/-20.4 mg/100g wet matter (WM) soluble oxalate and 220.1+/-96.5mg/100g WM insoluble oxalate. The frozen spinach contained 90mg total calcium/100g WM, 76.7%of this calcium was unavailable as it was bound to oxalate as insoluble oxalate. The oxalate/calcium (mEq) ratio of the frozen spinach was 4.73. When frozen convenience food is grilled there is no opportunity for the soluble oxalates to be leached out into the cooking water and discarded. Soluble oxalates, when consumed, have the ability to bind to calcium in the spinach and any calcium in foods consumed with the spinach, reducing the absorption of soluble oxalate. In this experiment 10 volunteers ingested 100g grilled spinach alone or with 100g additions of cottage cheese, sour cream and sour cream with Calci-Trim milk (180 g) and finally, with 20g olive oil. The availability of oxalate in the spinach was determined by measuring the oxalate output in the urine over a 6-hour and 24-hour period after intake of the test meal. The mean bioavailability of soluble oxalate in the grilled spinach was 0.75+/-0.48% over a 6-hour period after intake and was 1.93+/-0.85% measured over a 24-hour period. Addition of sour cream and Calci-Trim milk reduced the availability of the oxalate in the spinach significantly (P<0.05) in both the 6-hour and 24-hour collection periods.

Adult↗
PubMed1989

Oxalate metabolism in renal stone disease with special reference to calcium metabolism and intestinal absorption.

Hyperoxaluria and hypercalciuria are common features of renal calcium stone disease. The purpose of the present investigation was to examine the relationships between the intestinal absorption and the renal handling of oxalate and calcium in patients with idiopathic renal stone disease and in patients with enteric hyperoxaluria following jejunoileal bypass (JIB), in comparison with healthy controls. Hyperoxaluria was associated with a higher frequency of both stone episodes and stone operations than a lower urinary oxalate concentration. Patients with idiopathic stone disease showed increased intestinal uptake of both oxalate and calcium, which was probably of importance for their propensity to form calcium oxalate-containing stones. Hyperoxaluria in patients with JIB was found to be a result of hyperabsorption of oxalate, and these patients displayed altered oxalate kinetics with continued urinary excretion of orally administered 14C-oxalate for more than 48 hours. The prolonged excretion is assumed to be due to a prolonged absorption and/or an increased oxalate pool. Malabsorption of calcium and low fasting urinary calcium excretion in the JIB patients were associated with high tubular reabsorption of calcium, the latter presumably attributable to a compensatory increase in circulating parathyroid hormone (PTH). In most recurrent renal stone formers the urinary calcium concentration was increased, with an inverse relationship to serum PTH, indicating intestinal hyperabsorption of calcium. A subgroup of hypercalciuric patients showed increased urinary calcium due to reduced tubular reabsorption of calcium. It is suggested that this is a renal defect resulting in a compensatory rise in PTH. Two different mechanisms of similar prevalence might explain enhanced secretion of PTH in normocalcaemic stone disease, namely reduced calcium absorption and a renal defect in the form of reduced tubular reabsorption of calcium. Glycosaminoglycans efficiently inhibit calcium oxalate crystal growth by binding to the surface of calcium oxalate crystals. In this study the binding was dependent on ionic strength. Higher affinity to the crystals may be the reason why highly charged glycosaminoglycans were more efficient inhibitors of calcium oxalate crystal growth. A calcium-containing organic marine hydrocolloid with the capacity to bind oxalate in vitro was shown to reduce enteric hyperoxaluria. In addition to biochemical effects considerable improvements in diarrhoeal symptoms were reported.

Adult↗
PubMed2003

Changes in renal hemodynamics and urodynamics in rats with chronic hyperoxaluria and after acute oxalate infusion: role of free radicals.

AIMS: The aim of this study was to evaluate possible changes in renal hemodynamic and urodynamic parameters in rats with chronic hyperoxaluria and after acute oxalate challenge. We also evaluated the possible association between free radical (FR) production, hyperoxaluria, and calcium oxalate (CaOx) calculi formation. METHODS: Chronic hyperoxaluria was induced by adding 0.75% ethylene glycol (EG) to the drinking water of male Wistar rats. After 7, 21, and 42 days of treatment, urinary biochemistry, oxalate levels, and lipid peroxides were measured. Kidney calculi were examined by polarizing microscopy. In the second part of the experiments, 1, 10, 20, and 30 mg kg(-1) hr(-1) oxalate was infused, by means of an intrarenal arterial catheter (IRA), into normal rats sequentially. Superoxide dismutase (SOD) infusion by means of IRA, in addition to oxalate, was also performed to check its influence on the altered renal function after oxalate infusion. In both the acute and chronic groups, renal blood flow (RBF), cortical microvascular blood flow (CMVBF), glomerular filtration rate (GFR), urine flow (UV), and urinary sodium excretion (U(Na)V) were measured, and chemiluminescence (CL) was examined in the renal venous blood. RESULTS: Levels of urinary lipid peroxides and enzymuria had increased since day 7, and increased the size of numbers of CaOx crystals in the kidney were noted beginning on day 21, but elevated CL was detectable only on day 7 after 0.75% EG treatment. Decreased UV and U(Na)V were noted in the 42-day EG group, although the 24-hr creatinine clearance values were normal in all experimental groups. On the other hand, RBF, GFR, and CMVBF were attenuated with elevated FR when the oxalate concentration was higher than 10 mg kg(-1) hr(-1) in the acute oxalate infusion group. With SOD pretreatment, the decreased RBF, GFR, and CMVBF could be reversed at 10 mg kg(-1) hr(-1) of oxalate, and be partially reversed at 20. FR also could be reduced significantly at 10 and 20 mg kg(-1) hr(-1) of oxalate. CONCLUSIONS: Decreased urine flow and sodium excretion were the main renal functions affected by chronic hyperoxaluria. However, that only the 42-day EG group had a decreased tubular function cannot be fully explained by the persistent tubular enzymuria and increased lipid peroxides that began on day 7 after EG treatment. With acute oxalate infusion, the major insult to renal function was renal hemodynamics. Pretreated SOD could reverse the attenuated hemodynamics and reduce the elevated FR partly, which suggested that FR is responsible for oxalate toxicity.

Acute Disease↗
PubMed1978

Renal handling of oxalate. A micropuncture study in the rat.

Clearance and micropuncture experiments were performed in rats to study the renal handling of oxalate. The 14C-oxalate to 3H-inulin clearance ratio (Cox/Cin) was 1.36 +/- 0.04 and was lowered by probenecid (200 mg/kg) to 1.11 +/- 0.03 (+/- S.E., n = 6, P less than 0.005). An attempt was made to localize the assumed secretion of oxalate in three different micropuncture protocols. In free flow micropuncture experiments single nephron clearance of oxalate was not different when obtained from proximal or distal tubular puncture sites. The fractional delivery of oxalate averaged 0.84 +/- 0.03 regardless of the puncture site from mid-proximal to late distal. This finding indicates a net outflux of oxalate in an early proximal loop since oxalate is freely ultrafilterable. In microperfusion experiments the mean recovery of oxalate ranged from 79--90%. The outflux of oxalate correlated linearly with the tubular load (r = 0.95). The results suggest that no net secretion occurs in superficial nephron segments accessible for micropuncture. Since whole kidney clearances of oxalate always exceeded glomerular filtration rate, it is concluded that net addition of oxalate into the tubular fluid can occur at sites beyond the superficial late distal tubules or is due to higher delivery of oxalate by deep cortical nephrons.

Animals↗
PubMed2005

Effects of oxalate exposure on Madin-Darby canine kidney cells in culture: renal prothrombin fragment-1 mRNA expression.

It has been suggested that renal tubular cell damage induced by oxalic acid, one of the components of urinary calculi, may be involved in a variety of ways in the development of urolithiasis. During our study on a calculus related protein, renal prothrombin fragment-1 (RPTF-1), we noted that this is an inflammation related substance that mediates an acute inflammatory reaction, one of the original roles of prothrombin. RPTF-1 is a part of prothrombin that is a coagulation factor known to be expressed in the renal tubule. We examined whether oxalic acid may cause cytotoxic effects on tubular epithelial cells and whether such chemical stimulation may promote the translation of RPTF-1 mRNA into RPTF-1 proteins. We used Madin-Darby canine kidney (MDCK) cells derived from the distal tubule of a dog kidney. In this study, the effects of oxalic acid in culture solution at different concentrations on cytotoxicity were assessed using a MTT assay. The location of active oxygen species was identified using dichlorofluorescein diacetate. After the prothrombin sequence of RPTF-1 was confirmed in MDCK cells, RPTF-1 mRNA expression was determined by RT-PCR. The gene sequence of the same promoter area was ligated, and a luciferase sequence was inserted downstream of the vector. The target sequence was transfected into MDCK cells and the relation between oxalic acid and prothrombin promoter was examined. In addition, the variable expression of RPTF-1 mRNA was quantitatively compared depending on oxalic acid concentrations using real-time PCR. When cytotoxicity was investigated, cells were not damaged but, by contrast, were stimulated and activated under oxalic acid below a certain concentration. The relation between cytotoxicity on the cultured MDCK cell membrane and active oxygen species was confirmed. Luminescence in MDCK cells containing the luciferase gene was detected by the addition of oxalic acid, which activated the prothrombin promoter. A part of the prothrombin gene sequence in the MDCK cells was detected and an increase in the expression of RPTF-1 mRNA in MDCK cells by the addition of oxalic acid was confirmed using real-time PCR. Increased expression of prothrombin by adding oxalic acid has already been demonstrated in previous studies. In this study, however, RPTF-1 mRNA was promoted by oxalic acid and a direct association between oxalic acid and RPTF-1 is indicated. This finding shows that increased oxalic acid in urine induces the expression of RPTF-1 in tubular epithelial cells and thereby causes the generation of active oxygen species.

Animals↗
PubMed2001

Characterization of recombinant barley oxalate oxidase expressed by Pichia pastoris.

Oxalate oxidase catalyzes the oxidation of oxalate to carbon dioxide and hydrogen peroxide, making it useful for clinical analysis of oxalate in biological fluids. An artificial gene for barley oxalate oxidase has been used to produce functional recombinant enzyme in a Pichia pastoris heterologous expression system, yielding 250 mg of purified oxalate oxidase from 5 L of fermentation medium. The recombinant oxalate oxidase was expressed as a soluble, hexameric 140 kDa glycoprotein containing 0.2 g-atom Mn/monomer with a specific activity of 10 U/mg, similar to the properties reported for enzyme isolated from barley. No superoxide dismutase activity was detected in the recombinant oxalate oxidase. EPR spectra indicate that the majority of the manganese in the protein is present as Mn(II), and are consistent with the six-coordinate metal center reported in the recent X-ray crystal structure for barley oxalate oxidase. The EPR spectra change when bulky anions such as iodide bind, indicating conversion to a five-coordinate complex. Addition of oxalate perturbs the EPR spectrum of the Mn(II) sites, providing the first characterization of the substrate complex. The optical absorption spectrum of the concentrated protein contains features associated with a minor six-coordinate Mn(III) species, which disappears on addition of oxalate. EPR spin-trapping experiments indicate that carboxylate free radicals (CO2*-) are transiently produced by the enzyme in the presence of oxalate, most likely during reduction of the Mn(III) sites. These features are incorporated into a turnover mechanism for oxalate oxidase.

Carboxylic Acids↗
PubMed1992

Determination of evolved 14CO2 in decarboxylase reactions with application to measurement of [14C]oxalic acid.

An assay is described for the determination of the radioactive purity of [14C]oxalic acid preparations and the quantity of [14C]oxalic acid in biological samples. In this method oxalate decarboxylase is used to convert oxalate to formate and CO2. The entire procedure is carried out in a scintillation vial. The 14CO2 released in the enzymic reaction is allowed to diffuse off in a fume hood following acidification. Scintillation fluid is added to reacted and unreacted vials and the radioactivity measured. The loss of radioactivity from the reacted versus the unreacted vials provides the quantity of evolved 14CO2. This value is equal to 50% of the [14C]-oxalate (dpm) present. The radioactive purity of four preparations of [U-14C]oxalic acid was 99.0% while a fifth batch had a purity of 88%. A single batch of [U-14C]oxalic acid had a radioactive purity of 99.0% following storage of an aqueous solution, at -20 degrees C for 7 years. Recovery of [14C]oxalic acid from rat fecal extracts was 101.3%. Eight replicate analyses of a [U-14C]oxalic acid preparation gave a coefficient of variation of 0.3%. Following subcutaneous infusion of [U-14C]oxalic acid to rats, 100.2 +/- 2.9%, mean +/- SD, of the 14C in fecal extracts was present as [14C]oxalic acid (n = 10). The procedure provides a rapid, sensitive, and specific method to determine [14C]oxalic acid. It avoids the time consuming and inconvenient procedure for trapping and counting the evolved 14CO2. The approach used to determine the evolved 14CO2 may find application in other radiochemical methods that require its measurement.

Animals↗
PubMed2004

Oxalobacter formigenes and its role in oxalate metabolism in the human gut.

Oxalate is ingested in a wide range of animal feeds and human foods and beverages and is formed endogenously as a waste product of metabolism. Bacterial, rather than host, enzymes are required for the intestinal degradation of oxalate in man and mammals. The bacterium primarily responsible is the strict anaerobe Oxalobacter formigenes. In humans, this organism is found in the colon. O. formigenes has an obligate requirement for oxalate as a source of energy and cell carbon. In O. formigenes, the proton motive force for energy conservation is generated by the electrogenic antiport of oxalate(2-) and formate(1-) by the oxalate-formate exchanger, OxlT. The coupling of oxalate-formate exchange to the reductive decarboxylation of oxalyl CoA forms an 'indirect' proton pump. Oxalate is voided in the urine and the loss of O. formigenes may be accompanied by elevated concentrations of urinary oxalate, increasing the risk of recurrent calcium oxalate kidney stone formation. Links between the occurrence of nephrolithiasis and the presence of Oxalobacter have led to the suggestion that antibiotic therapy may contribute to the loss of this organism from the colonic microbiota. Studies in animals and human volunteers have indicated that, when administered therapeutically, O. formigenes can establish in the gut and reduce the urinary oxalate concentration following an oxalate load, hence reducing the likely incidence of calcium oxalate kidney stone formation. The findings to date suggest that anaerobic, colonic bacteria such as O. formigenes, that are able to degrade toxic compounds in the gut, may, in future, find application for therapeutic use, with substantial benefit for human health and well-being.

Animals↗
PubMed1975

Magnetic resonance and kinetic studies of pyruvate, phosphate dikinase. Interaction of oxalate with the phosphorylated form of the enzyme.

Pyruvate, orthophosphate dikinase (EC 2.7.9.1) carries out its catalytic function in three successive partial reactions, the final step being the reaction of pyruvate with a stable phosphoenzyme intermediate to give phosphoenolpyruvate and free enzyme (Evans, H.J., and Wood, H. G. (1968), Proc. Natl. Acad. Sci. U.S.A. 61, 1448). Interactions of oxalate, a structural analog of enolpyruvate, with the phosphorylated form of the enzyme have been investigated by kinetic inhibition measurements and by magnetic resonance studies of manganous ion complexes with the enzyme. Oxalate inhibits the reaction catalyzed by pyruvate, phosphate dikinase, and the inhibition is linearly competitive with respect to pyruvate. The inhibitor constant for oxalate of 25 mu-M is fourfold lower than the Michaelis constant for pyruvate. The enhancement in the longitudinal relaxation rate of water protons (PRR) which occurs upon binding of Mn(II) to the enzyme has been used to monitor binding of oxalate to Mn(II)-enzyme complexes. PRR titrations indicate that the dissociation constant of oxalate from the Mn(II) complex of the free form of the enzyme is an order of magnitude weaker than the kinetically determined Ki. On the other hand, titrations of solutions which contain the phosphorylated form of the enzyme reveal a much stronger binding of oxalate. Moreover, the strength of oxalate binding to the phosphorylated enzyme is a function both of the species and of the concentration of monovalent cations in the solution. In the presence of Tl+, which has the most favorable activator constant for the final partial reaction, the dissociation constant for oxalate from its complex with the phosphorylated enzyme is less than 1 mu-M. Electron paramagnetic resonance (EPR) spectra for the enzyme-bound Mn(II) are sensitive to structural perturbations which occur upon binding of substrates or of oxalate to the enzyme. The EPR spectrum for the Mn(II)-phosphoenzyme-oxalate species is distinguished from spectra for other complexes of the enzyme by unusually narrow line widths and consequent resolution of fine structure from electronic quadrupole splitting. The narrow lines in the EPR spectrum are indicative of a rigid, pseudocrystalline environment for the bound Mn(II). The magnitude and frequency dependence of the PRR for the Mn(II)-phosphoenzyme-oxalate complex indicate that if any water molecules are bound to the Mn(II), their exchange with the bulk water is severely retarded. The kinetic and magnetic resonance studies support the hypothesis that oxalate mimics the reactive intermediate, enolpyruvate, in a complex with the phosphorylated enzyme which may resemble the structure of the transition state of the final partial reaction.

Bacillus↗
PubMed1995

Erythrocyte transmembrane flux and renal clearance of oxalate in idiopathic calcium nephrolithiasis.

An anomaly in erythrocyte oxalate transport has been reported in patients with idiopathic calcium oxalate nephrolithiasis. Even if clinical and experimental evidence suggests a causal role of this cellular anomaly in calcium nephrolithiasis, a definitive answer to this fundamental question is still lacking. We approached this problem by searching for a possible relationship between the erythrocyte oxalate self-exchange anomaly and the renal clearance of this anion in stone formers. In 10 idiopathic calcium-oxalate renal stone formers, and 10 healthy subjects we evaluated the erythrocyte oxalate flux rate, and the renal fractional clearance of oxalate by a recently described enzymathic procedures for plasma oxalate determination. With respect to controls, stone formers had higher oxalate flux rate in erythrocytes, and higher oxalate renal fractional clearance with a significant direct correlation between the two parameters. These data are compatible with a membrane transport abnormality within the kidney of these stone formers, and the existence of a common defect of the oxalate transport shared by both erythrocytes and tubular renal cells. The latter may be crucial in the pathogenesis of calcium oxalate nephrolithiasis, by modifying the renal handling of oxalate.

Adult↗
PubMed2000

Effects of an extract from Herniaria hirsuta on calcium oxalate crystallization in vitro.

OBJECTIVE: To evaluate the effectiveness of an extract obtained from Herniaria hirsuta on calcium oxalate crystallization in vitro. Materials and methods An extract was prepared from H. hirsuta at different concentrations (0.0625-1 mg/mL). Crystallization was induced in whole normal human urine samples in the absence or presence of the extract. Crystals generated in the urine were harvested and analysed by scanning electron microscopy. The nucleation and aggregation of calcium oxalate crystals were measured separately using spectrophotometric methods. The nucleation rate was followed at 620 nm after mixing calcium chloride and sodium oxalate solution at 37 degrees C, with stirring. The induction time in the presence of herb extract was compared with that of the control. The aggregation rate was also followed at 620 nm in a buffered solution containing calcium oxalate monohydrate crystals after stopping the stirring. The rate was evaluated by comparing the slope of turbidity in the presence of the extract with that of the control. RESULTS: The herb extract promoted the precipitation of calcium oxalate particles in whole urine. SEM showed that there were more crystals with increasing concentration of extract but that they were proportionally smaller. Moreover, the presence of herb extract favoured the formation of calcium oxalate dihydrate rather than monohydrate crystals. The extract inhibited calcium oxalate crystal aggregation. In an independent experiment, the herb extract was dialysed and filtered before inducing crystallization, to eliminate any fibrous particles and oxalate. The treated herb extract promoted more crystallization, especially at high concentrations. CONCLUSION: An extract of H. hirsuta promoted the nucleation of calcium oxalate crystals, increasing their number but decreasing their size. It also promoted the formation of calcium oxalate dihydrate crystals, despite the presence of calcium oxalate monohydrate particles. The extract may contain substances that inhibit calcium oxalate crystal aggregation. These properties of H. hirsuta might be beneficial in preventing kidney stone formation.

Calcium Oxalate↗
PubMed2002

Effects of oxalate on the re-initiation of DNA synthesis in LLC-PK1 cells do not involve p42/44 MAP kinase activation.

BACKGROUND: Oxalate interaction with renal epithelial cells results in a program of events that include alterations in gene expression, re-initiation of DNA synthesis, cell growth and apoptosis. Our studies focused on understanding the mechanisms involved in the oxalate-induced re-initiation of the DNA synthesis. The effects of oxalate alone or in combination with epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and insulin were investigated to determine whether oxalate utilized the p42/44 mitogen activated protein (MAP) kinase pathway, which is a common pathway used by a majority of the mitogens. METHODS: LLC-PK1 cells (a renal epithelial cell line of porcine origin) were exposed to oxalate in the presence or absence of three established growth factors, EGF, insulin and PDGF, and of the transcription/translation inhibitors, actinomycin-D and cycloheximide. DNA synthesis was assessed by [3H]-thymidine incorporation. p42/44 MAP kinase activity was assessed by super-shift analysis as well as by immunocomplex kinase assay. RESULTS: Exposure of growth-arrested LLC-PK1 cells to oxalate resulted in the re-initiation of the DNA synthesis was abolished by [corrected] pretreatment with transcription/translation inhibitors. Oxalate (1 mmol/L), EGF (50 ng/mL) and insulin (100 ng/mL) stimulated DNA synthesis in growth-arrested LLC-PK1 cells, while PDGF (50 ng/mL) had no effect. Effects of EGF and oxalate on DNA synthesis were additive. In contrast, oxalate and insulin had antagonistic effects on DNA synthesis. Additionally, oxalate did not activate the p42/44 MAP kinase pathway while EGF stimulated this pathway. CONCLUSIONS: These findings demonstrate that oxalate does not activate the p42/44 MAP kinase pathway, and the effects of oxalate are mediated by pathways that are distinct from those of EGF, PDGF and insulin.

Animals↗
PubMed1999

Epidemiologic evidence for the role of oxalate in idiopathic nephrolithiasis.

The importance of dietary and urinary oxalate in the formation of calcium oxalate kidney stones is widely accepted. Although the epidemiologic evidence for the role of oxalate remains largely indirect, recent prospective observations suggest its importance. The inverse association between dietary calcium intake and the risk of stone formation may be attributable to decreased gastrointestinal absorption of dietary oxalate and, thus, lower urinary oxalate concentrations. Further, the decreased risk of stone formation in women who consume large doses of vitamin B6 may be secondary to decreased oxalate production. The increased risk of nephrolithiasis observed with increasing body size may also be secondary to increased endogenous oxalate production. However, the frequency of hyperoxaluria is not substantially different in cases and controls for either sex. Notably, men have both higher stone incidence rates and higher mean urinary oxalate concentrations than women. Additional studies are needed to determine more precisely the role of dietary oxalate. More valid and comprehensive information on the oxalate content of food are desperately needed. Because the data on dietary oxalate are inconclusive, the routine restriction of dietary oxalate needs to be reexamined.

Calcium Oxalate↗
PubMed1978

Oxalic acid metabolism in the rat.

Feeding experiments indicated that approximately 15% of dietary oxalate is adsorbed in the rat intestine and that dietary oxalate accounts for about one third of the oxalic acid normally excreted in rat urine. Oxalate excretion increased by about 40% when a low calcium diet was fed, decreased by 65% when a low protein diet was fed and increased by 100% when a high protein diet was fed. Fasting for 24 hours resulted in a fall in calcium excretion but phosphate and creatinine excretion increased. Oxalate excretion also tended to increase. Between 60% and 70% of activity was recovered in the urine, faeces and body tissues after 14C-oxalic acid had been administered intraperitoneally. Recoveries of 14C-labeled compounds as urinary 14C-oxalic acid decreased in the following order: glyoxylic acid greater than ascorbic acid greater than citric acid greater than glycollic acid greater than tryptophan greater than hydroxyproline greater than glycine. It is suggested that conversion of citrate to oxalate in the rat may occur via the "glyoxylate cycle." It is concluded that a higher proportion of dietary oxalate is absorbed in the rat intestine compared with man, and that dietary oxalate accounts for a higher proportion of urinary oxalate in the rat than in man. Intestinal secretion and bacterial degradation of oxalate also appear to be proportionately greater in the rat than in man.

Animals↗
PubMed2005

Oxalate stimulates IL-6 production in HK-2 cells, a line of human renal proximal tubular epithelial cells.

BACKGROUND: Oxalate is a metabolic end product excreted primarily by the kidney and associated with several pathologic conditions. The most common pathologic condition involving oxalate is the formation of calcium oxalate stones in the kidney. Several stimuli have been implicated in the development of glomerular and tubular injury in various forms of immune-mediated renal diseases. The elevated level of interleukin-6 (IL-6) has been reported in the urine of kidney stone-forming patients. In the present study, we investigated the role of oxalate, a major constituent of calcium oxalate kidney stone disease, in the production of IL-6 in normal human HK-2 kidney cells. METHODS: Confluent cultures of HK-2 cells (a renal epithelial cell line of human origin) were exposed to various concentrations of oxalate (0.2 to 2.0 mmol/L) and lipopolysaccharide (LPS) (0.1 and 10 mug/mL) for various time points (4-24 h) under serum-free conditions. The conditioned mediums were collected, and an IL-6 protein level was measured by enzyme-linked immunosorbent assay (ELISA). The total cellular RNA was isolated from the cells and subjected to relative quantitative reverse transcription-polymerase chain reaction (RT-PCR) to determine the expression of IL-6 mRNA. The statistical analysis of the results was carried out using the Student t test. RESULTS: HK-2 cells express IL-6 mRNA and protein. Oxalate increased the secretion of IL-6 protein in HK-2 cells in a concentration-dependent fashion. Oxalate exposure to HK-2 cells also induced transcriptional up-regulation of the IL-6 gene, as determined by the increased level of IL-6 mRNA expression following treatment with oxalate. Moreover, the effects of oxalate on IL-6 expression were time- and concentration-dependent. This is the first report demonstrating the regulation of IL-6 by oxalate. CONCLUSION: This study provides the first direct evidence that oxalate up-regulates the expression and secretion of IL-6 in renal epithelial cells. The increased IL-6 expression and secretion by renal epithelial cells may play a critical role in the progression of urolithiasis in hyperoxaluric conditions.

Cell Line↗