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• W2786001144 abstract "Most kidney stones are composed of calcium oxalate, and minor changes in urine oxalate affect the stone risk. Obesity is a risk factor for kidney stones and a positive correlation of unknown etiology between increased body size, and elevated urinary oxalate excretion has been reported. Here, we used obese ob/ob (ob) mice to elucidate the pathogenesis of obesity-associated hyperoxaluria. These ob mice have significant hyperoxaluria (3.3-fold) compared with control mice, which is not due to overeating as shown by pair-feeding studies. Dietary oxalate removal greatly ameliorated this hyperoxaluria, confirming that it is largely enteric in origin. Transporter SLC26A6 (A6) plays an essential role in active transcellular intestinal oxalate secretion, and ob mice have significantly reduced jejunal A6 mRNA (- 80%) and total protein (- 62%) expression. While net oxalate secretion was observed in control jejunal tissues mounted in Ussing chambers, net absorption was seen in ob tissues, due to significantly reduced secretion. We hypothesized that the obesity-associated increase in intestinal and systemic inflammation, as reflected by elevated proinflammatory cytokines, suppresses A6-mediated intestinal oxalate secretion and contributes to obesity-associated hyperoxaluria. Indeed, proinflammatory cytokines (elevated in ob mice) significantly decreased intestinal oxalate transport in vitro by reducing A6 mRNA and total protein expression. Proinflammatory cytokines also significantly reduced active mouse jejunal oxalate secretion, converting oxalate transport from net secretion in vehicle-treated tissues to net absorption in proinflammatory cytokines-treated tissues. Thus, reduced active intestinal oxalate secretion, likely secondary to local and systemic inflammation, contributes to the pathogenesis of obesity-associated hyperoxaluria. Hence, proinflammatory cytokines represent potential therapeutic targets. Most kidney stones are composed of calcium oxalate, and minor changes in urine oxalate affect the stone risk. Obesity is a risk factor for kidney stones and a positive correlation of unknown etiology between increased body size, and elevated urinary oxalate excretion has been reported. Here, we used obese ob/ob (ob) mice to elucidate the pathogenesis of obesity-associated hyperoxaluria. These ob mice have significant hyperoxaluria (3.3-fold) compared with control mice, which is not due to overeating as shown by pair-feeding studies. Dietary oxalate removal greatly ameliorated this hyperoxaluria, confirming that it is largely enteric in origin. Transporter SLC26A6 (A6) plays an essential role in active transcellular intestinal oxalate secretion, and ob mice have significantly reduced jejunal A6 mRNA (- 80%) and total protein (- 62%) expression. While net oxalate secretion was observed in control jejunal tissues mounted in Ussing chambers, net absorption was seen in ob tissues, due to significantly reduced secretion. We hypothesized that the obesity-associated increase in intestinal and systemic inflammation, as reflected by elevated proinflammatory cytokines, suppresses A6-mediated intestinal oxalate secretion and contributes to obesity-associated hyperoxaluria. Indeed, proinflammatory cytokines (elevated in ob mice) significantly decreased intestinal oxalate transport in vitro by reducing A6 mRNA and total protein expression. Proinflammatory cytokines also significantly reduced active mouse jejunal oxalate secretion, converting oxalate transport from net secretion in vehicle-treated tissues to net absorption in proinflammatory cytokines-treated tissues. Thus, reduced active intestinal oxalate secretion, likely secondary to local and systemic inflammation, contributes to the pathogenesis of obesity-associated hyperoxaluria. Hence, proinflammatory cytokines represent potential therapeutic targets. Kidney stone (KS) disease is the second most prevalent kidney disease in the USA after hypertension, with a rising prevalence and complications including chronic kidney disease and end-stage renal disease.1Alexander R.T. Hemmelgarn B.R. Wiebe N. et al.Kidney stones and kidney function loss: a cohort study.BMJ. 2012; 345: e5287Crossref PubMed Scopus (186) Google Scholar It remains a major source of patient discomfort and disability, lost working days, and health care expenditure (∼$10 billion annually). Hyperoxaluria is a major risk factor for KS disease, and 70% to 80% of kidney stones are composed of calcium oxalate (CO).2Coe F.L. Evan A. Worcester E. Kidney stone disease.J Clin Investig. 2005; 115: 2598-2608Crossref PubMed Scopus (574) Google Scholar Urinary oxalate is an important determinant of supersaturation, and the risk for stone formation is affected by small changes in urine oxalate.3Curhan G.C. Taylor E.N. 24-h uric acid excretion and the risk of kidney stones.Kidney Int. 2008; 73: 489-496Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar Obesity is a leading, preventable cause of death worldwide, with increasing prevalence in adults and children, and is reaching an epidemic level in the United States. Obesity is a critical causative factor in the development of metabolic syndrome (MS).4Gorbachinsky I. Akpinar H. Assimos D.G. Metabolic syndrome and urologic diseases.Rev. Urol. 2010; 12: e157-e180PubMed Google Scholar Obesity and MS are associated with higher rates of KS in several studies.4Gorbachinsky I. Akpinar H. Assimos D.G. Metabolic syndrome and urologic diseases.Rev. Urol. 2010; 12: e157-e180PubMed Google Scholar, 5Rendina D. Mossetti G. De Filippo G. et al.Association between metabolic syndrome and nephrolithiasis in an inpatient population in southern Italy: role of gender, hypertension and abdominal obesity.Nephrol Dial Transplant. 2009; 24: 900-906Crossref PubMed Scopus (90) Google Scholar, 6West B. Luke A. Durazo-Arvizu R.A. et al.Metabolic syndrome and self-reported history of kidney stones: the National Health and Nutrition Examination Survey (NHANES III) 1988-1994.Am J Kidney Dis. 2008; 51: 741-747Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar Although a greater proportion of KS in obese patients are uric acid stones, COKS are also common in these patients, as reported by Li et al.7Li W.M. Chou Y.H. Li C.C. et al.Association of body mass index and urine pH in patients with urolithiasis.Urol Res. 2009; 37: 193-196Crossref PubMed Scopus (49) Google Scholar who found that 53.1% of uric acid stone formers were obese compared with 42.7% of COKS formers. Mild to moderate hyperoxaluria is frequently seen in obese stone formers, and a positive correlation between increased body size and elevated urinary oxalate excretion has been reported in population-based studies.8Taylor E.N. Curhan G.C. Determinants of 24-hour urinary oxalate excretion.Clin J Am Soc Nephrol. 2008; 3: 1453-1460Crossref PubMed Scopus (122) Google Scholar, 9Lemann Jr, J. Pleuss J.A. Worcester E.M. et al.Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults.Kidney Int. 1996; 49: 200-208Abstract Full Text PDF PubMed Scopus (193) Google Scholar, 10Kleinman J.G. Bariatric surgery, hyperoxaluria, and nephrolithiasis: a plea for close postoperative management of risk factors.Kidney Int. 2007; 72: 8-10Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar Urinary oxalate is significantly higher in COKS formers with MS than in those without MS (353 ± 141 μmol/d in those without MS but 454 ± 206 μmol/d in those with MS), and it significantly rises with increasing features of MS (356 ± 141 to 504 ± 203 μmol/d; 0–4 features).11Sakhaee K. Capolongo G. Maalouf N.M. et al.Metabolic syndrome and the risk of calcium stones.Nephrol Dial Transplant. 2012; 27: 3201-3209Crossref PubMed Scopus (47) Google Scholar In addition, analysis of individuals with and without KS in the Nurses’ Health Study I (NHSI), Nurses’ Health Study II (NHSII), and Health Professionals Follow-up Study (HPFS), revealed that urinary oxalate excretion is directly related to body mass index in women.12Taylor E.N. Curhan G.C. Body size and 24-hour urine composition.Am J Kidney Dis. 2006; 48: 905-915Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar Moreover, overweight children have significantly higher urine oxalate than children with normal weight.13Sarica K. Eryildirim B. Yencilek F. et al.Role of overweight status on stone-forming risk factors in children: a prospective study.Urology. 2009; 73: 1003-1007Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar A reduced man-to-woman KS ratio, from 1.7:1 in 1997 to 1.3:1 in 2002, was reported, in which a greater increase in overweight and obese women than men was posited as a possible explanation for the changing trend.14Scales Jr., C.D. Curtis L.H. Norris R.D. et al.Changing gender prevalence of stone disease.J Urol. 2007; 177: 979-982Abstract Full Text Full Text PDF PubMed Scopus (223) Google Scholar The mechanism(s) underlying the positive correlation between body size and urinary oxalate excretion and, hence, increased incidence of KS disease, beyond dietary indiscretion, remain(s) unknown. With the rising prevalence of obesity and MS, it is expected that the incidence of KS disease will continue to increase at a significant rate, leading to a substantial increase in care costs. Better understanding of the mechanisms underlying the obesity-associated hyperoxaluria (OAH) is crucial for identification of potential targets for therapeutic intervention. To this end, we initiated studies using the obese ob/ob (ob) mouse, an animal model extensively used in obesity studies in which the obesity is primarily due to leptin deficiency,15Lindstrom P. The physiology of obese-hyperglycemic mice [ob/ob mice].ScientificWorldJournal. 2007; 7: 666-685Crossref PubMed Scopus (238) Google Scholar and observed that these mice have significantly higher incidence of hyperoxaluria than their lean controls. We found that reduced active transcellular intestinal oxalate secretion, which is likely mediated by proinflammatory cytokines (PCs), contributes to OAH. We also found that several PCs significantly reduce SLC26A6 (A6)-mediated oxalate transport, both in vitro and in vivo. To make measurements of oxalate more convenient, oxalate uptake and not efflux (secretion) has been determined in human colonic human epithelial colorectal adenocarcinoma (Caco2-BBE [C2]) cells, as A6 operates in both directions.16Jiang Z. Grichtchenko I.I. Boron W.F. et al.Specificity of anion exchange mediated by mouse Slc26a6.The Journal of biological chemistry. 2002; 277: 33963-33967Crossref PubMed Scopus (151) Google Scholar We used ob mice to elucidate the molecular mechanisms underlying the positive correlation between body size and urinary oxalate excretion8Taylor E.N. Curhan G.C. Determinants of 24-hour urinary oxalate excretion.Clin J Am Soc Nephrol. 2008; 3: 1453-1460Crossref PubMed Scopus (122) Google Scholar, 9Lemann Jr, J. Pleuss J.A. Worcester E.M. et al.Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults.Kidney Int. 1996; 49: 200-208Abstract Full Text PDF PubMed Scopus (193) Google Scholar To establish ob mice as a useful model for OAH, we assessed whether ob mice have increased urinary oxalate excretion compared to that in their lean controls. As shown in Figure 1a, ob mice have 3.3-fold higher urine oxalate (adjusted for creatinine) compared to that in controls, using urine samples collected directly from the bladders at the time of killing or collected over a 1-h period (see Methods). Importantly, we also observed 3.2-fold higher urine oxalate in ob mice compared to that in controls using 24-h urine samples collected by placing the mice in metabolic cages (Figure 1b). These results show that ob mice have similar levels of hyperoxaluria when urinary oxalate is adjusted for creatinine, which corrects for any variations in urinary water excretion, or expressed as an excretion rate over 24 h. Collectively, these results indicate that the ob mice have significant hyperoxaluria and therefore establishes them as a useful model to elucidate the mechanisms of OAH. Mice deficient in leptin receptor, db/db (db) mice, are another animal model commonly used for studying obesity.17Wua J. Wang H.M. Li J. et al.[The research applications of db/db mouse].Sheng li ke xue jin zhan. [Progress in physiology.]. 2013; 44: 12-18PubMed Google Scholar We similarly assessed urinary oxalate levels in db mice and their controls to ensure that the observed hyperoxaluria was not specific to the ob mice. Interestingly, db mice have 2.3-fold higher urine oxalate than their lean controls (Figure 2), indicating the hyperoxaluria observed in the ob mice is not specific to these mice. ob and db mice are hyperphagic, and therefore it is highly possible that the observed hyperoxaluria is largely the result of diet. To control for this possibility, ob mice and their controls were housed individually (1 mouse/cage), and their daily food consumption was assessed over a period of 4 days, during which they had free access to food. The ob mice consumed significantly higher amounts (1.8-fold) of food per day than controls (Figure 3a). To rule out the possibility that the observed hyperoxaluria was due to overeating, the ob mice and their controls were pair-fed (4 g/mouse per day) for up to 4 days, with the pair-fed mice in the 2 groups consuming all the food. Importantly, the ob mice were still found to have 2.6-fold higher urine oxalate than controls (Figure 3b). Taken together, these results strongly support the hypothesis that the observed hyperoxaluria is largely due to specific defect(s) in the ob mice, and it is clearly not solely due to overeating. The anion exchanger SLC26A6 (A6) is apically expressed in enterocytes and plays an essential role in small intestinal active transcellular oxalate secretion, thereby preventing hyperoxaluria and related KS disease (A6 null mice develop hyperoxalemia, hyperoxaluria, and KS)18Freel R.W. Hatch M. Green M. et al.Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6 null mice.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G719-G728Crossref PubMed Scopus (143) Google Scholar, 19Jiang Z. Asplin J.R. Evan A.P. et al.Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6.Nat Genet. 2006; 38: 474-478Crossref PubMed Scopus (251) Google Scholar SLC26A2 (A2) is also apically expressed in enterocytes, and it transports oxalate when expressed in heterologous systems20Haila S. Hastbacka J. Bohling T. et al.SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types.J Histochem Cytochem. 2001; 49: 973-982Crossref PubMed Scopus (70) Google Scholar, 21Satoh H. Susaki M. Shukunami C. et al.Functional analysis of diastrophic dysplasia sulfate transporter. Its involvement in growth regulation of chondrocytes mediated by sulfated proteoglycans.J Biol Chem. 1998; 273: 12307-12315Crossref PubMed Scopus (128) Google Scholar, 22Alper S.L. Sharma A.K. The SLC26 gene family of anion transporters and channels.Mol Aspects Med. 2013; 34: 494-515Crossref PubMed Scopus (236) Google Scholar; however, its role in intestinal oxalate transport is unknown. In addition, SLC26A3 (A3) is also apically expressed in enterocytes and plays a critical role in mouse intestinal active transcellular oxalate absorption.23Freel R.W. Whittamore J.M. Hatch M. Transcellular oxalate and Cl- absorption in mouse intestine is mediated by the DRA anion exchanger Slc26a3, and DRA deletion decreases urinary oxalate.Am J Physiol Gastrointest Liver Physiol. 2013; 305: G520-G527Crossref PubMed Scopus (47) Google Scholar Active transcellular intestinal oxalate secretion requires oxalate influx into the enterocyte from the blood side, where SLC26A1 (A1) is likely to be involved, and then its efflux from the luminal side by A6 (with or without other transporters, potentially including A2). Therefore, we evaluated whether there was altered mRNA expression of 1 or more of these transporters in intestinal tissues from the ob mice by using quantitative polymerase chain reaction (qPCR) analysis. Interestingly, jejunal A6 mRNA expression was significantly reduced (80%) in ob mice compared with that in controls, without a change in A1, A2, and A3 mRNA expression levels (Figure 4). These results indicate that the observed decrease in A6 mRNA was specific and not due to global changes in mRNA expression in the ob mice. To evaluate whether the observed reduction in A6 mRNA expression was translated into decreased A6 protein expression, A6 total protein expression was assessed by immunoblotting. Indeed, the ob mice had significantly reduced (62%) jejunal A6 total protein expression compared to that in controls (Figure 5a and b ). Due to lack of good antibodies, we did not assess A1, A2, and A3 total protein expression. Of note is that we did not observe a significant change in the expression of the apical membrane protein villin (data not shown). Because A6 plays a crucial role in small intestinal oxalate secretion,18Freel R.W. Hatch M. Green M. et al.Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6 null mice.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G719-G728Crossref PubMed Scopus (143) Google Scholar, 19Jiang Z. Asplin J.R. Evan A.P. et al.Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6.Nat Genet. 2006; 38: 474-478Crossref PubMed Scopus (251) Google Scholar it is possible that the reduced jejunal A6 mRNA and total protein expression could lead to decreased active intestinal oxalate secretion and therefore potentially contribute to the observed hyperoxaluria. To test this possibility, jejunal tissues were isolated from the ob mice and their controls and mounted in Ussing chambers. Of note, the jejunum was chosen because jejunal wall inflammation was reported in the db mice,24Duparc T. Naslain D. Colom A. et al.Jejunum inflammation in obese and diabetic mice impairs enteric glucose detection and modifies nitric oxide release in the hypothalamus.Antioxidants Redox Signal. 2011; 14: 415-423Crossref PubMed Scopus (35) Google Scholar and which we confirmed in our ob mice (see Figure 8b ), as well as the fact that A6 is highly expressed in mouse jejunum (at an equivalent level to that in the duodenum).25Wang Z. Petrovic S. Mann E. et al.Identification of an apical Cl(-)/HCO3(-) exchanger in the small intestine.Am J Physiol Gastrointest Liver Physiol. 2002; 282: G573-G579Crossref PubMed Scopus (226) Google Scholar Interestingly, although a net oxalate secretory flux (−14 ± 11 pmol/h/cm2) was observed in control tissues, a large net oxalate absorptive flux (16 ± 8 pmol/h/cm2) was seen in the ob tissues (Figure 6). This was mainly due to a significant reduction (31%) in jejunal serosa-to-mucosa (JSM]) oxalate secretion. In addition, we observed a nonsignificant increase (19%) in the absorptive flux (mucosa-to-serosa [JMS]) secretion, which also contributed to the reversal of oxalate transport from net secretion in control tissues to net absorption in ob tissues. Collectively, these findings indicate that reduced active transcellular intestinal oxalate secretion and potentially increased transcellular intestinal oxalate absorption contribute to the hyperoxaluria observed in ob mice and, hence, to the pathogenesis of OAH.Figure 7Effect of dietary oxalate removal on urinary oxalate levels in ob/ob (ob) mice and their lean controls. Urinary oxalate levels were assessed as described in the Methods in ob and control mice consuming an oxalate-containing diet (regular diet) or an oxalate-free diet. The oxalate-free diet significantly reduced urinary oxalate levels in the ob mice (*P < 8.2E–12 for the ob mice on the oxalate-free diet compared with the regular diet, by unpaired Student t test; n = 7–10).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 8Plasma and jejunal cytokine levels in the ob/ob (ob) mice and their lean controls. (a) Plasma TNF-α (TNF), IFN-γ (IFN), and IL-6 levels were measured as described in the Methods. Values are means ± SD of 10 to 19 independent measurements, each of which was made in duplicate. The ob mice have significantly higher plasma levels of TNF, IFN, and IL-6 (*P < 0.002, 3.2E–06, and 1.4E–09 for ob compared with controls, with regards to TNF, IFN, IL-6, respectively, by unpaired Student t test). (b) Jejunal total RNA was isolated from the ob mice and their controls for real-time polymerase chain reaction PCR analysis. Values are means ± SD of 7 to 11 independent experiments, each of which was done in triplicate. Relative TNF, IFN, and IL-6 mRNA expression levels were expressed as a percentage of control normalized to that of GAPDH. The ob mice have significantly higher jejunal wall TNF and IFN mRNA expression levels (*P < 0.002 and 0.008 for ob compared with controls, with regard to TNF and IFN, respectively, by unpaired Student t test). GAPDH, glyceraldehyde-3-phosphate dehydrogenase.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Reduced active intestinal oxalate secretion contributes to the pathogenesis of OAH by increasing the amount of net oxalate absorbed by the intestine and indicates that the OAH is mainly enteric in origin. To support the hypothesis that the OAH is enteric in origin, the ob mice and their controls were placed on an oxalate-free diet to evaluate the effect of dietary oxalate removal on the observed hyperoxaluria. As shown in Figure 7, an oxalate-free diet greatly ameliorated the observed hyperoxaluria, confirming that it is largely enteric in origin. Although the oxalate-free diet greatly ameliorated the observed hyperoxaluria, urine oxalate remains significantly higher (∼1.3-fold) in the ob mice than the urine oxalate in the control mice on a regular diet, suggesting that a small component of the observed hyperoxaluria may be due to increased endogenous hepatic oxalate synthesis. To evaluate whether increased hepatic oxalate synthesis contributes to the observed hyperoxaluria, urinary glycolate (an indicator of hepatic oxalate synthesis26Dawson P.A. Russell C.S. Lee S. et al.Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice.J Clin Investig. 2010; 120: 706-712Crossref PubMed Scopus (85) Google Scholar) levels in the ob mice and their controls were measured. There were no significant differences between glycolate levels in the ob mice and those in their controls (μg/mg creatinine: control = 86.5 ± 8; ob = 82.8 ± 6.9; n = 6), suggesting that the ob mice have no evidence of enhanced hepatic oxalate synthesis through a glycolate-dependant pathway. Obesity is characterized by chronic systemic inflammation,27Das U.N. Is obesity an inflammatory condition?.Nutrition. 2001; 17: 953-966Abstract Full Text Full Text PDF PubMed Scopus (639) Google Scholar and both ob and db mice have higher plasma levels of several PCs (e.g., TNF-α [TNF], IFN-γ [IFN], IL-1β, and IL-6).28Brun P. Castagliuolo I. Di Leo V. et al.Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis.Am J Physiol Gastrointest Liver Physiol. 2007; 292: G518-G525Crossref PubMed Scopus (666) Google Scholar Obesity is also characterized by increased small intestinal inflammation.24Duparc T. Naslain D. Colom A. et al.Jejunum inflammation in obese and diabetic mice impairs enteric glucose detection and modifies nitric oxide release in the hypothalamus.Antioxidants Redox Signal. 2011; 14: 415-423Crossref PubMed Scopus (35) Google Scholar, 29Veilleux A. Grenier E. Marceau P. et al.Intestinal lipid handling: evidence and implication of insulin signaling abnormalities in human obese subjects.Arterioscler Thromb Vasc Biol. 2014; 34: 644-653Crossref PubMed Scopus (61) Google Scholar To evaluate whether our ob mice had increased systemic and/or small intestinal wall inflammation under our housing conditions, plasma and jejunal TNF, IFN, and IL-6 levels were measured by enzyme-linked immunosorbent assay and qPCR, respectively. The ob mice were found to have significantly higher plasma levels of TNF, IFN, IL-6 (Figure 8a), and jejunal TNF and IFN (Figure 8b), confirming systemic and jejunal wall inflammation in these mice. The ob mice also had a nonsignificant increase in jejunal wall IL-6 levels. A6-mediated intestinal oxalate secretion plays a critical role in limiting net intestinal absorption of ingested oxalate, thereby preventing hyperoxaluria and KS.18Freel R.W. Hatch M. Green M. et al.Ileal oxalate absorption and urinary oxalate excretion are enhanced in Slc26a6 null mice.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G719-G728Crossref PubMed Scopus (143) Google Scholar, 19Jiang Z. Asplin J.R. Evan A.P. et al.Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6.Nat Genet. 2006; 38: 474-478Crossref PubMed Scopus (251) Google Scholar It is possible that the obesity milieu is associated with factors that could cause defective A6 regulation, leading to reduced active intestinal oxalate secretion. We hypothesized that the high circulating and intestinal PC expression levels observed in obesity, which inhibit several intestinal transporters,30Rocha F. Musch M.W. Lishanskiy L. et al.IFN-gamma downregulates expression of Na(+)/H(+) exchangers NHE2 and NHE3 in rat intestine and human Caco-2/bbe cells.Am J Physiol Cell Physiol. 2001; 280: C1224-C1232Crossref PubMed Google Scholar, 31Musch M.W. Clarke L.L. Mamah D. et al.T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase.J Clin Investig. 2002; 110: 1739-1747Crossref PubMed Scopus (153) Google Scholar suppress A6-mediated intestinal oxalate secretion and, thus, contribute to OAH. To test this hypothesis, we examined the effects of several PCs on apical oxalate uptake (≥49% of which is mediated by A632Freel R.W. Morozumi M. Hatch M. Parsing apical oxalate exchange in Caco-2BBe1 monolayers: siRNA knockdown of SLC26A6 reveals the role and properties of PAT-1.Am J Physiol Gastrointest Liver Physiol. 2009; 297: G918-G929Crossref PubMed Scopus (29) Google Scholar, 33Arvans D. Jung Y.C. Antonopoulos D. et al.Oxalobacter formigenes-derived bioactive factors stimulate oxalate transport by intestinal epithelial cells.J Am Soc Nephrol. :JASN. 2017; 28: 876-887Crossref PubMed Scopus (55) Google Scholar) by human intestinal Caco2-BBE cells. C2 cells were treated basolaterally with TNF (25 ng/ml × 48 h) and IFN, IL-6, or IL-β (50 ng/ml × 48 h) before assessing 14C-labeled oxalate ([14C]oxalate) uptake. TNF, IFN, and IL-6 significantly inhibited (30%, 33%, and 32%, respectively) apical [14C]oxalate uptake by C2 cells, whereas IL-1β had no effect (which reflects the specific inhibitory effects of TNF, IFN, and IL-6) (Figure 9). On the other hand, the PCs IL-2 and IL-8 (50 ng/ml × 48 h), which are elevated in obese human subjects,34Rosa J.S. Heydari S. Oliver S.R. et al.Inflammatory cytokine profiles during exercise in obese, diabetic, and healthy children.J Clin Res Pediatr Endocrinol. 2011; 3: 115-121Crossref PubMed Scopus (22) Google Scholar had no effect (data not shown). The PC concentrations were selected based on previous work30Rocha F. Musch M.W. Lishanskiy L. et al.IFN-gamma downregulates expression of Na(+)/H(+) exchangers NHE2 and NHE3 in rat intestine and human Caco-2/bbe cells.Am J Physiol Cell Physiol. 2001; 280: C1224-C1232Crossref PubMed Google Scholar, 35Fujiya M. Inaba Y. Musch M.W. et al.Cytokine regulation of OCTN2 expression and activity in small and large intestine.Inflamm Bowel Dis. 2011; 17: 907-916Crossref PubMed Scopus (25) Google Scholar, 36Vavricka S.R. Musch M.W. Fujiya M. et al.Tumor necrosis factor-alpha and interferon-gamma increase PepT1 expression and activity in the human colon carcinoma cell line Caco-2/bbe and in mouse intestine.Pflugers Arch. 2006; 452: 71-80Crossref PubMed Scopus (48) Google Scholar and on our findings in pilot studies (where several concentrations were tested), indicating that the described doses gave the best inhibition. Taken together, these results show that active DIDS-sensitive (100 μM DIDS inhibits it by 91% as we previously reported37Amin R. Sharma S. Ratakonda S. et al.Extracellular nucleotides inhibit oxalate transport by human intestinal Caco-2-BBe cells through PKC-delta activation.Am J Physiol Cell Physiol. 2013; 305: C78-C89Crossref PubMed Scopus (13) Google Scholar) apical [14C]oxalate uptake by C2 cells, is suppressed by several PCs. Because A6 mRNA and total protein expression levels were significantly reduced in the ob mice, we examined whether TNF, IFN, and/or IL-6 inhibit apical [14C]oxalate transport by C2 cells by reducing A6 mRNA and/or total protein expression level(s). Using qPCR, TNF, and IFN significantly reduced (38% and 36%, respectively) A6 mRNA expression, whereas IL-6 had no significant effect (Figure 10). These results show that TNF and IFN inhibit oxalate transport by C2 cells by reducing A6 mRNA expression. To confirm that the observed PC-induced reduction in A6 mRNA expression in C2 cells is translated into decreased A6 protein expression, A6 total protein expression was assessed by immunoblotting. TNF and IFN also significantly reduced A6 total protein expression in C2 cells (37% and 42%, respectively) (Figure 11). However, IL-6 had no significant effect on A6 total protein expression (d" @default.
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• W2786001144 title "Reduced active transcellular intestinal oxalate secretion contributes to the pathogenesis of obesity-associated hyperoxaluria" @default.
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• W2786001144 doi "https://doi.org/10.1016/j.kint.2017.11.011" @default.
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