Renal toxicity of ethylene glycol results from internalization of calcium oxalate crystals by proximal tubule cells

Hovda, Knut Erik; Guo, Chungang; Austin, Ronald L.; McMartin, Kenneth E.

doi:10.1016/j.toxlet.2009.11.013

Cited by 62 publications

(69 citation statements)

References 34 publications

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“…The progression starts in glomeruli with loss of separation of tuft and Bowman's capsule by forming cell bridge passing on damage from lost and/or damaged nephrons to so far healthy kidney (Xue et al, 2005). Similar to our ultrastructure result, Smith et al (1990), Fan et al (1999) and Hovda et al (2009), reported a change in Bowman's capsule and glomerular tufts including shrinkage of glomeruli, glomerulosclerosis, widening of space beneath the Bowman's capsule, decreased number of glomeruli and thickened glomerular basement membrane with the prominent vesicular cytoplasm.…”

Section: Discussionsupporting

confidence: 87%

Antiurolithic and antihypertensive activities of Origanum vulgaris on urolithic rats

ElSawy¹,

Shaheen²,

Filimban³

et al. 2015

J. Med. Plants Res.

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Origanum vulgaris (Oregano) has been used in the fluky medicinal for treating various diseases including urolithiasis and hypertension. This study was designed to investigate the possible antioxidant and antiurolithic activities of different standardized extracts of Oregano ethanol extract n-hexane, ethyl acetate, and aqueous fraction on rats. The dried hydroalcoholic extract of 70% ethyl alcohol Oregano was suspended in water and successively extracted with n-hexane and ethyl acetate. Each active extract was screened of phytochemical and standardized spectrophotometricaly by estimation of total phenol and total flavonoid content. Antiurolithic and antioxidant activities were studied on live rat model by oral doses of ethylene glycol and NH 4 Cl. The active extracts of Oregano (20 mg/kg) were given to different groups and one group without extracts was used as control. At the end of the experimental period, blood samples were obtained from studying biochemical parameters and a kidney specimen for histopathology using scanning electron microscope. Ethanol extract, n-hexane and aqueous fractions prevented as well as opposed toxic changes, including loss of body weight gain and appetite, raised serum urea, uric acid and creatinine levels, and crystal deposition in the kidneys. These potential urolithitic effects of ethylene glycol should be taken into considerations with close monitoring of kidney function tests at frequent intervals. The oregano antioxidant effect might be more effective in the amelioration of ethylene glycol induced kidney injury and urolithiasis.

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Section: Discussionsupporting

confidence: 87%

Antiurolithic and antihypertensive activities of Origanum vulgaris on urolithic rats

ElSawy¹,

Shaheen²,

Filimban³

et al. 2015

J. Med. Plants Res.

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“…The treatment time of 6 hours in this study is consistent with that described in previous studies on kidney stones. 22,23 We selected the concentrations of H 2 O 2 and crystals based on the following reasons. The commonly used H 2 O 2 concentration to induce cell injury ranged from 10 to 1,000 μmol/L.…”

Section: Cell Culturementioning

confidence: 99%

Reinjury risk of nano-calcium oxalate monohydrate and calcium oxalate dihydrate crystals on injured renal epithelial cells: aggravation of crystal adhesion and aggregation

Gan¹,

Sun²,

Bhadja³

et al. 2016

IJN

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Background Renal epithelial cell injury facilitates crystal adhesion to cell surface and serves as a key step in renal stone formation. However, the effects of cell injury on the adhesion of nano-calcium oxalate crystals and the nano-crystal-induced reinjury risk of injured cells remain unclear. Methods African green monkey renal epithelial (Vero) cells were injured with H 2 O 2 to establish a cell injury model. Cell viability, superoxide dismutase (SOD) activity, malonaldehyde (MDA) content, propidium iodide staining, hematoxylin–eosin staining, reactive oxygen species production, and mitochondrial membrane potential (Δψm) were determined to examine cell injury during adhesion. Changes in the surface structure of H 2 O 2 -injured cells were assessed through atomic force microscopy. The altered expression of hyaluronan during adhesion was examined through laser scanning confocal microscopy. The adhesion of nano-calcium oxalate monohydrate (COM) and calcium oxalate dihydrate (COD) crystals to Vero cells was observed through scanning electron microscopy. Nano-COM and COD binding was quantitatively determined through inductively coupled plasma emission spectrometry. Results The expression of hyaluronan on the cell surface was increased during wound healing because of Vero cell injury. The structure and function of the cell membrane were also altered by cell injury; thus, nano-crystal adhesion occurred. The ability of nano-COM to adhere to the injured Vero cells was higher than that of nano-COD crystals. The cell viability, SOD activity, and Δψm decreased when nano-crystals attached to the cell surface. By contrast, the MDA content, reactive oxygen species production, and cell death rate increased. Conclusion Cell injury contributes to crystal adhesion to Vero cell surface. The attached nano-COM and COD crystals can aggravate Vero cell injury. As a consequence, crystal adhesion and aggregation are enhanced. These findings provide further insights into kidney stone formation.

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“…[12][13][14] The ability to induce cell death is closely linked with the degree of cellular internalization of COM crystals. 12 EG is metabolized fairly rapidly, so there is little time between ingestion and the formation of the toxic metabolites; thus, quick and aggressive treatment is required. 2,15 With early diagnosis, inhibition of the enzyme alcohol dehydrogenase using fomepizole or ethanol can block the metabolism of EG, effectively preventing the formation of COM.…”

Section: Introductionmentioning

confidence: 99%

“…3,4 Experiments using kidney cell cultures have convincingly shown that COM, and not the metabolites glycolate, glyoxylate, or ionic oxalate, is the metabolite responsible for the renal toxicity associated with EG poisoning. [5][6][7][8][9] COM crystals can bind to kidney cell membranes and can be internalized by kidney cells, 7,[10][11][12] where they induce mitochondrial dysfunction leading to cell death. [12][13][14] The ability to induce cell death is closely linked with the degree of cellular internalization of COM crystals.…”

mentioning

confidence: 99%

“…[5][6][7][8][9] COM crystals can bind to kidney cell membranes and can be internalized by kidney cells, 7,[10][11][12] where they induce mitochondrial dysfunction leading to cell death. [12][13][14] The ability to induce cell death is closely linked with the degree of cellular internalization of COM crystals. 12 EG is metabolized fairly rapidly, so there is little time between ingestion and the formation of the toxic metabolites; thus, quick and aggressive treatment is required.…”

mentioning

confidence: 99%

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Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

Besenhofer

Cain

Dunning

et al. 2012

Journal of the American Society of Nephrology

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Calcium oxalate monohydrate crystals are responsible for the kidney injury associated with exposure to ethylene glycol or severe hyperoxaluria. Current treatment strategies target the formation of calcium oxalate but not its interaction with kidney tissue. Because aluminum citrate blocks calcium oxalate binding and toxicity in human kidney cells, it may provide a different therapeutic approach to calcium oxalateinduced injury. Here, we tested the effects of aluminum citrate and sodium citrate in a Wistar rat model of acute high-dose ethylene glycol exposure. Aluminum citrate, but not sodium citrate, attenuated increases in urea nitrogen, creatinine, and the ratio of kidney to body weight in ethylene glycol-treated rats. Compared with ethylene glycol alone, the addition of aluminum citrate significantly increased the urinary excretion of both crystalline calcium and crystalline oxalate and decreased the deposition of crystals in renal tissue. In vitro, aluminum citrate interacted directly with oxalate crystals to inhibit their uptake by proximal tubule cells. These results suggest that treating with aluminum citrate attenuates renal injury in rats with severe ethylene glycol toxicity, apparently by inhibiting calcium oxalate's interaction with, and retention by, the kidney epithelium. Ethylene glycol (EG) is a common household poison found in antifreeze, automotive engine coolants, and water-based latex paints. Approximately 5000 accidental or intentional EG ingestions occur per year in the United States, resulting in about 20-30 deaths. 1 Acute EG poisoning can result in central nervous system depression, metabolic acidosis, acute renal failure, coma, and death. 2 Ethylene glycol itself is nontoxic. However, the end metabolite, oxalate, is insoluble in the presence of calcium and forms oxalate crystals (primarily calcium oxalate monohydrate [COM]) that are deposited in the kidney tissue. Pathologic studies have shown that COM accumulation in the tubule correlates strongly with the degree of proximal tubule cell necrosis and with renal failure. 3,4 Experiments using kidney cell cultures have convincingly shown that COM, and not the metabolites glycolate, glyoxylate, or ionic oxalate, is the metabolite responsible for the renal toxicity associated with EG poisoning. 5-9 COM crystals can bind to kidney cell membranes and can be internalized by kidney cells, 7,10-12 where they induce mitochondrial dysfunction leading to cell death. [12][13][14] The ability to induce cell death is closely linked with the degree of cellular internalization of COM crystals. 12 EG is metabolized fairly rapidly, so there is little time between ingestion and the formation of the toxic metabolites; thus, quick and aggressive treatment is required. 2,15 With early diagnosis, inhibition of the enzyme alcohol dehydrogenase using fomepizole or ethanol can block the metabolism of EG, effectively preventing the formation of COM. If renal failure has already occurred, longterm hemodialysis (2-6 months) must be used to

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Renal toxicity of ethylene glycol results from internalization of calcium oxalate crystals by proximal tubule cells

Cited by 62 publications

References 34 publications

Antiurolithic and antihypertensive activities of Origanum vulgaris on urolithic rats

Antiurolithic and antihypertensive activities of Origanum vulgaris on urolithic rats

Reinjury risk of nano-calcium oxalate monohydrate and calcium oxalate dihydrate crystals on injured renal epithelial cells: aggravation of crystal adhesion and aggregation

Aluminum Citrate Prevents Renal Injury from Calcium Oxalate Crystal Deposition

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