| Objective: To investigate the difference of acute nephrotoxicity between mice and rats when exposed to high-dose microcystin-RR and to further explore their underlying mechanism.Method: In the first stage,The LD50 of SD rats injected intraperitoneally with microcystin-RR was 766.213 mu g/kg,and its 95% confidence interval was(747.329 g/kg ~ 785.097g/kg).KM male mice and SD male rats were divided into four groups at random,with 6mice per group.All animals were allowed to acclimatize to their surrounding conditions for10 days,and the body weight,urine volume and water intake were measured daily.MC-RR was diluted with physiological saline and administered to the rats at doses of 574.66 ?g/kg,287.33 ?g/kg,143.67 ?g /kg,and 0 ?g/kg BW via intraperitoneal route for single injection.The same administration of MC-RR to the mice was performed at doses of 210 ?g/kg,105?g/kg,52.5 ?g/kg,and 0 ?g/kg BW.During the administration period,urine volume and water intake were measured.After the 24 th hour,the animals were euthanized to investigate the damage of the liver and kidney and detect the expression of Oatps in the liver and kidney by fluorescence quantitative PCR method.In the second stage,the experiments were performed on a new batch of 30 SD rats(in 5 groups,n=6)to investigate the effect of dexamethasone(DXM)on the nephritis induced by the high dose of MC-RR.The groups of animals were treated with dosages of DXM 5 mg/m L+MC-RR 574.66 ?g/kg,DXM 1mg/m L+MC-RR 574.66 ?g/kg,DXM 0.2 mg/m L+MC-RR 574.66 ?g/kg,MC-RR 574.66?g/kg and physiological saline(Group E).After the 24 th hour,the animals were euthanized to investigate whether the damage of the kidney was alleviated.Results: In the first stage of the experiments,the symptoms of an increased urine output and hematuresis were observed in rats in the high dose group.However,signs of polyuria and hematuresis were not observed either in the other groups of rats or in all groups of the mice throughout the experiment.Furthermore,serious kidney injury of rats were observed in the high dose group,such as increased weight of kidney,obvious inflammatory nephrocytes and erythrocyte diapedesis,disruption of normal structure of the kidney,increased serum CREA and decreased serum UA,macroscopic hematuresis,and the abnormal levels of leukocyte and protein in the urine.The increase in liver weight and serious liver injury,such as obvious swelling and inflammatory hepatocytes,several areas of hemorrhage and necrosis in the liver and the increase in serum enzymes like LDH,ALT,AST,ALP,were observed in the rats treated with 574.66 ?g/kg MC-RR compared with the control(P<0.01).The serum biochemical tests showed that AST was significantly higher in the rats treated with 287.33?g/kg MC-RR compared with the control group(P<0.01).A relatively slight liver damage,such us the swelling hepatocytes,and the increases in serum enzymes like LDH,ALT,AST,ALP,were observed in the mice treated with 210 ?g/kg MC-RR compared with the control(P<0.05).However,signs of renal injury were not observed throughout the experiment in mice,such as BUN,CREA,UA,and histopathology observation being in normal ranges.In the second stage,the symptoms of kidney injure like polyuria and hematuresis induced by the high dose of MC-RR returned to normal when the subjects were administered with 5mg/m L DXM.In addition,the observed polyuria and hematuresis induced by MC-RR could be alleviated by DXM in a dose-dependent manner.The m RNA level of Oatp1a1 was highly expressed in liver and kidney both in mice and in rats,with a relatively higher expression in the liver.Oatp1a3 was only highly expressed in rat kidney.Oatp2a1 was expressed almost the same level in mouse liver and kidney and a relatively higher expression level in rat liver than kidney.Oatp3a1 was expressed higher in rat liver than kidney and the opposite in mice was observed,in which Oatp3a1 was expressed higher in kidney.Oatp4a1 expressed in rat liver was nearly 2 times as many as in rat kidney.Oatp1b2 was mainly expressed in mouse and rat liver.Oatp2b1 was expressed almost the same level in rat liver and kidney and a relatively higher expression level in mouse liver than kidney.Oatp1c1 was expressed higher in rat kidney than liver.Conclusion: A single high doses of microcystins-RR can induce serious rat kidney injury and obvious phenomena of polyuria and hematuria.However,signs of renal injury were not observed in mice.The different types of Oatps in the kidneys of mice and rats might be responsible for the obvious inconsistency observed between mice and rats in nephrotoxicity induced by MC-RR.The assumptions require further exploration.Hepatotoxity caused by high dosage of MC-RR can be observed both in mice and in rats with varying degrees of damage. |
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