Involvement of urinary proteins in the rat strain difference in sensitivity to ethylene glycol-induced renal toxicity

Li, Yan; McLaren, Marie C.; McMartin, Kenneth E.

doi:10.1152/ajprenal.00419.2009

Cited by 9 publications

(8 citation statements)

References 53 publications

(66 reference statements)

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“…Finally, a hyperoxaluria rat model induced by EG was used to assess the effects of oxalate on renal tubular epithelial cell injury and CaOx crystal depositions in vivo [27] . TEM assay showed that the number of autophagic vacuoles, including autophagosome and autolysosome, is significantly increased in model rats compared with control rats ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney

et al. 2018

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Hyperoxaluria-induced oxidative injury of renal tubular epithelial cell is a casual and essential factor in kidney calcium oxalate (CaOx) stone formation. Autophagy has been shown to be critical for the regulation of oxidative stress-induced renal tubular injury; however, little is known about its role in kidney CaOx stone formation. In the present study, we found that the autophagy antagonist chloroquine could significantly attenuate oxalate-induced autophagy activation, oxidative injury and mitochondrial damage of renal tubular cells in vitro and in vivo, as well as hyperoxaluria-induced CaOx crystals depositions in rat kidney, whereas the autophagy agonist rapamycin exerted contrasting effects. In addition, oxalate-induced p38 phosphorylation was significantly attenuated by chloroquine pretreatment but was markedly enhanced by rapamycin pretreatment, whereas the protective effect of chloroquine on rat renal tubular cell oxidative injury was partly reversed by a p38 protein kinase activator anisomycin. Furthermore, the knockdown of Beclin1 represented similar effects to chloroquine on oxalate-induced cell oxidative injury and p38 phosphorylation in vitro. Taken together, our results revealed that autophagy inhibition could attenuate oxalate-induced oxidative injury of renal tubular cell and CaOx crystal depositions in the rat kidney via, at least in part, inhibiting the activation of p38 signaling pathway, thus representing a novel role of autophagy in the regulation of oxalate-induced renal oxidative injury and CaOx crystal depositions for the first time.

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Section: Resultsmentioning

confidence: 99%

“…The kidney sections were processed for immunohistochemistry as described previously [27] . Antibodies against Beclin1, SQSTM1/P62, phospho-p38, p38, 8-OHdG and SOD1(Abcam Inc) were used for these experiments.…”

Section: Methodsmentioning

confidence: 99%

Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney

et al. 2018

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“…The renal damage caused by COM crystal deposition in the kidney may provoke an inflammatory response [36] in which the injured renal tubule cells and macrophages produce various cytokines including OPN [5], which was highly expressed in the renal tissue of the treatment group to attract and retain in the inflammatory cells at the site of inflammation as it coats COM crystals and mediates their attachment to macrophages and interstitial multinucleated cell to facilitate the removal of crystals and tissue repair [37]. But the multifunctional protein, OPN, tasks never end as at the same time it assists in the engulfment of crystals into macrophages and also protects the neighboring healthy tissue from the cytotoxic effect substances such as nitric oxide produced by macrophages [38].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical localization and mRNA quantification of osteopontin and Tamm-Horsfall protein in canine renal tissue after potassium oxalate injection

et al. 2014

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BackgroundUrinary macromolecules contribute to promoting or inhibiting crystal retention in renal tissue and stone formation. Osteopontin (OPN) and Tamm-Horsfall protein (THP) are the most important proteins involved in this process. Although these two proteins were discovered a long time ago, their role in setting kidney stone formation has not yet been fully investigated. We conducted a study to explore the role of OPN and THP in canine renal oxalosis. Ten dogs were carefully examined prior to the study. Six dogs were assigned to the treatment group and were injected intravenously with 0.5 M potassium oxalate (KOx). The other four dogs were assigned to a control group and were injected intravenously with 0.9% NaCl three times a day (tid) for 7 consecutive days. Then kidneys were harvested for pathological, immunohistochemical examination and OPN and THP mRNA expression levels were quantified by quantitative real-time PCR.ResultsCalcium oxalate crystals deposition was observed in both renal cortex and medulla. Immunohistochemistry examination revealed increased tissue expression of OPN in the renal tissue while THP was significantly decreased. OPN mRNA expression level significantly increased in treated dogs compared to that in the controls, while THP mRNA level significantly decreased.ConclusionTogether, these results suggest that THP and OPN are both involved in the pathogenesis and response to oxalate exposure.

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“…Most recent studies have used the Wistar strain because of the known strain difference in ethylene glycol (EG) toxicity (Cruzan et al, 2004), and the historical idea that the renal damage from DEG might result from the metabolism to EG, which then would produce the renal damage. This rat strain difference was initially demonstrated with a chronic low-dose EG administration, where F344 rats required twice as much EG to elicit renal damage (Cruzan et al, 2004) and where EG exposure produced calcium oxalate monohydrate (COM) crystal retention only in Wistar rats (Li et al, 2010). Although recent studies have shown that EG and oxalate do not have significant roles in the renal damage from DEG (Besenhofer at al., 2010; Besenhofer et al, 2011), the present studies were needed to elucidate if a strain difference also exists with DEG toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…As one important and related example, male Wistar rats have been shown to have increased sensitivity to ethylene glycol (EG)-induced nephrotoxicity, about double that of male F-344 rats (Cruzan et al, 2004). EG-treated Wistar rats have increased renal calcium oxalate crystal retention, as well as higher plasma oxalate levels (Li and McMartin, 2009; Corley et al, 2008; Li et al, 2010). In fact, the most recent DEG studies were done in male Wistar rats specifically to maximize the potential for a role of EG (calcium oxalate) in mediating the renal toxicity of DEG.…”

Section: Introductionmentioning

confidence: 99%

Diethylene glycol-induced toxicities show marked threshold dose response in rats

Landry

Dunning

Abreo

et al. 2015

Toxicology and Applied Pharmacology

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Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUN and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments.

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Involvement of urinary proteins in the rat strain difference in sensitivity to ethylene glycol-induced renal toxicity

Cited by 9 publications

References 53 publications

Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney

Autophagy inhibition attenuates hyperoxaluria-induced renal tubular oxidative injury and calcium oxalate crystal depositions in the rat kidney

Immunohistochemical localization and mRNA quantification of osteopontin and Tamm-Horsfall protein in canine renal tissue after potassium oxalate injection

Diethylene glycol-induced toxicities show marked threshold dose response in rats

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