Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020500 (hyperoxaluria)
 912 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An association between small bowel resection and stone disease has been noted, which is primarily due to increased gut oxalate absorption and resulting excretion by the kidney. In order to better understand the factors affecting both oxalate absorption and renal excretion, and the resulting renal lesions, we have developed a rodent model of small bowel resection and hyperoxaluria. Using this model, we have studied the renal histology in animals with hyperoxaluria over time spans from 2 weeks to 7 months. The initial lesion appears to be crystal formation along the brush border of the proximal tubule, with eventual crystal deposition in collecting ducts and papillary interstitium, and eventual tubule obstruction, interstitial inflammation and fibrosis. Crystal formation appears to dissociate from urinary supersaturation. We hypothesize that oxalate transporters in the proximal tubule may increase local saturations, leading to crystal formation at this site initially. Further studies are required to better characterize the causes and consequences of hyperoxaluria in this animal model.
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PMID:A new animal model of hyperoxaluria and nephrolithiasis in rats with small bowel resection. 1628 81

The majority of the Na(+) and Cl(-) filtered by the kidney is reabsorbed in the proximal tubule. In this nephron segment, a significant fraction of Cl(-) is transported via apical membrane Cl(-)-base exchange: Cl(-)-formate exchange, Cl(-)-oxalate exchange, Cl(-)-OH(-) exchange, and Cl(-)-HCO(3)(-) exchange. A search for the transporter responsible for apical membrane Cl(-)-formate exchange in the proximal tubule led to the identification of CFEX (SLC26A6). Functional expression studies in Xenopus oocytes demonstrated that CFEX is capable of mediating not only Cl(-)-formate exchange but also Cl(-)-oxalate exchange, Cl(-)-OH(-) exchange, and Cl(-)-HCO(3)(-) exchange. Studies in CFEX-null mice have begun to elucidate which of the anion exchange activities mediated by CFEX is important for renal physiology and pathophysiology in vivo. Measurements of transport in renal brush border vesicles isolated from CFEX-null mice demonstrated that CFEX primarily mediates Cl(-)-oxalate exchange rather than Cl(-)-formate exchange. Microperfusion studies in CFEX-null mice revealed that CFEX plays an essential role in mediating oxalate-dependent NaCl absorption in the proximal tubule. CFEX-null mice were found to have hyperoxaluria and a high incidence of calcium oxalate urolithiasis. The etiology of hyperoxaluria in CFEX-null mice was observed to be a defect in oxalate secretion in the intestine, leading to enhanced net absorption of ingested oxalate and elevation of plasma oxalate. Thus, by virtue of its function as a Cl(-)-oxalate exchanger, CFEX plays essential roles both in proximal tubule NaCl transport and in the prevention of hyperoxaluria and calcium oxalate nephrolithiasis.
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PMID:Essential roles of CFEX-mediated Cl(-)-oxalate exchange in proximal tubule NaCl transport and prevention of urolithiasis. 1688 19

Rats with small bowel resection fed a high-oxalate diet develop extensive deposition of calcium oxalate (CaOx) and calcium phosphate crystals in the kidney after 4 mo. To explore the earliest sites of renal crystal deposition, rats received either small bowel resection or transection and were then fed either standard chow or a high-oxalate diet; perfusion-fixed renal tissue from five rats in each group was examined by light microscopy at 2, 4, 8, and 12 wk. Rats fed the high-oxalate diet developed birefringent microcrystals at the brush border of proximal tubule cells, with or without cell damage; the lesion was most common in rats with both resection and a high-oxalate diet (10/19 with the lesion) and was significantly correlated with urine oxalate excretion (P < 0.001). Rats with bowel resection fed normal chow had mild hyperoxaluria but high urine CaOx supersaturation; four of these rats developed birefringent crystal deposition with tubule plugging in inner medullary collecting ducts (IMCD). Two rats fed a high-oxalate diet also developed this lesion, which was correlated with CaOx supersaturation, but not oxalate excretion. Tissue was examined under oil immersion, and tiny birefringent crystals were noted on the apical surface of IMCD cells only in animals with IMCD crystal plugging. In one animal, IMCD crystals were both birefringent and nonbirefringent, suggesting a mix of CaOx and calcium phosphate. Overall, these animals demonstrate two distinct sites and mechanisms of renal crystal deposition and may help elucidate renal lesions seen in humans with enteric hyperoxaluria and stones.
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PMID:Pathophysiological correlates of two unique renal tubule lesions in rats with intestinal resection. 1702 59

The brush border Cl--oxalate exchanger SLC26A6 plays an essential role in mediating intestinal secretion of oxalate and is crucial for the maintenance of oxalate homeostasis and the prevention of hyperoxaluria and calcium oxalate nephrolithiasis. Previous in vitro studies have suggested that SLC26A6 is heavily N-glycosylated. N-linked glycosylation is known to critically affect folding, trafficking, and function in a wide variety of integral membrane proteins and could therefore potentially have a critical impact on SLC26A6 function and subsequent oxalate homeostasis. Through a series of enzymatic deglycosylation studies we confirmed that endogenously expressed mouse and human SLC26A6 are indeed glycosylated, that the oligosaccharides are principally attached via N-glycosidic linkage, and that there are tissue-specific differences in glycosylation. In vitro cell culture experiments were then used to elucidate the functional significance of the addition of the carbohydrate moieties. Biotinylation studies of SLC26A6 glycosylation mutants indicated that glycosylation is not essential for cell surface delivery of SLC26A6 but suggested that it may affect the efficacy with which it is trafficked and maintained in the plasma membrane. Functional studies of transfected SLC26A6 demonstrated that glycosylation at two sites in the putative second extracellular loop of SLC26A6 is critically important for chloride-dependent oxalate transport and that enzymatic deglycosylation of SLC26A6 expressed on the plasma membrane of intact cells strongly reduced oxalate transport activity. Taken together, these studies indicated that oxalate transport function of SLC26A6 is critically dependent on glycosylation and that exoglycosidase-mediated deglycosylation of SLC26A6 has the capacity to profoundly modulate SLC26A6 function.
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PMID:N-glycosylation critically regulates function of oxalate transporter SLC26A6. 2809 52