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Nephrotoxicity is a dose-limiting factor in clinical use of cisplatin. The changes in renal haemodynamics were suggested to play a role in cisplatin-induced nephrotoxicity. The aim of the present study was to investigate the effect of modulation of nitric oxide on the severity of cisplatin-induced nephrotoxicity using an experimental rat model. A nitric oxide precursor, L-arginine and an inhibitor of nitric oxide synthase, L-NAME were used. After six days of cisplatin injection, acute nephrotoxicity was demonstrated by a marked increase in serum creatinine and blood urea nitrogen. Histological examination of the kidneys confirmed the occurrence of renal damage. Moreover, cisplatin induced an increase in the level of lipid peroxides and oxidized glutathione and a depletion of reduced glutathione. The activities of the antioxidant enzymes glutathione peroxidase and superoxide dismutase were also lowered. Besides, there was a reduction in the kidney total nitrate/nitrite levels. L-arginine significantly attenuated the oxidative stress and nephrotoxic effect of cisplatin. On the other hand, L-NAME was found to aggravate cisplatin nephrotoxicity. In conclusion, the decrease in the kidney nitric oxide level contributes, at least in part, in the mechanism underlying the nephrotoxicity of cisplatin. Furthermore, L-arginine shows nephroprotective effects and might be useful in improving the therapeutic index of cisplatin

Background: In the present study, we investigated the possible modulatory effect of losartan, an angiotensin receptor blocker, on oxidative stress induced by cisplatin (CDDP) as well as on CDDP uptake by the kidney. Methods: Rats were injected with a single dose of CDDP (7 mg/kg) and/or losartan (in either a single dose of 60 mg/kg or divided doses (10 mg/kg daily for 6 days), starting 1 h before CDDP injection. In addition, rat renal cortical slices were incubated with CDDP (2 mM) and/or losartan (2 mM) for 4 h. Nephrotoxicity was evaluated by measuring serum creatinine and blood urea nitrogen (BUN) in vivo and lactate dehydrogenase (LDH) leakage in vitro; histopathological examination of kidney tissue was also done. Oxidative stress markers including reduced glutathione (GSH) and lipid peroxides were also assessed. Furthermore, CDDP uptake by renal cortical slices was determined. Results: Losartan has protective effects against CDDP-induced nephrotoxicity as evidenced by restoration of normal serum levels of creatinine and BUN, and LDH leakage. Histopathological examination of the kidney confirmed these results. Also, losartan significantly counteracted CDDP-induced lipid peroxidation and GSH depletion. However, losartan did not affect CDDP uptake by the kidney. Conclusion: Our results indicate that losartan has proved to be a promising drug for clinical use as a nephroprotectant against CDDP-induced nephrotoxicity.

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Mangiferin, present in Mangifera indica bark, was reported to produce hypoglycemic and antidiabetic activity in an animal model of genetic type 2 diabetes and in streptozotocin diabetic rats. Its effect on diabetic insulinresistant animals has not been investigated. The current work aimed to explore the effect of mangiferin on diabetic insulin-resistant rat model. Diabetes was induced by high-fat/high fructose diet for eight weeks followed by a subdiabetogenic dose of streptozotocin (HFD-Fr-STZ). Rats were treated with mangiferin (20 mg/kg i.p.) for 28 days starting one week after STZ and its effects were compared to the standard insulin sensitizer, rosiglitazone. HFD-Fr-STZ, induced obesity, hyperglycemia and insulin resistance accompanied by depletion in liver glycogen and dyslipidemia. Moreover, there was an elevation in serum TNF-α and a reduction in adiponectin. Mangiferin ameliorated the consequences of HFD-Fr-STZ and its actions were comparable to the effects of the standard insulin sensitizer, rosiglitazone. The results obtained in this study provide evidence that mangiferin is a possible beneficial natural compound for type 2 diabetes and metabolic disorders associated with the metabolic syndrome. This effect is mediated through improving insulin sensitivity, modulating lipid profile and reverting adipokine levels to normal.