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The aim of the present study was to determine the protective effect of peanut shell extract (EPS) on rats with acute renal failure(ARF)and possible mechanism of protection. Acute renal failure was induced by glycerol , which was injected intramuscularly in rats. Healthy male SD rats were randomly divided into 4 groups: ARF + NS group, ARF + EPS group, NS + NS group and NS + EPS group. The level of renal function, which was reflect by blood urea nitrogen (BUN) and creatinine (Cre) levels, was determined using biochemical methods. The mechanism was explored by measuring the effects of malondialdehyde(MDA), glutathione(GSH) and nitric oxide(NO) levels in serum or kidney, as well as on the involvement of nitric oxide synthases (NOS) in the hypothalamic paraventricular nucleus. After injection of glycerol in rats, BUN, Cre and NO levels of ARF rats were significantly increased, as well as MDA in renal cortical homogenate and in serum. GSH levels were significantly lower in renal cortical homogenate and in serum. Immunohistochemistry showed that an obvious increase of neuronal nitric oxide synthase- immunoreactivity(nNOS-IR) in the hypothalamic paraventricular nucleus; Pretreatment with EPS in ARF rats caused BUN and Cre levels significantly lower. But compared with the NS + NS group, no significant difference between groups of rats. GSH in serum and renal cortical were observed significantly increased. Renal cortex homogenate MDA levels were significantly lower, however NO levels in renal cortex were significantly increased; nNOS-IR in the hypothalamic paraventricular nucleus were further enhanced, significantly higher than the ARF group. The results indicated peanut shell extract significantly improved renal function in rats with ARF, significantly reduced renal oxidative damage and increased NO levels, nNOS-IR in the hypothalamic paraventricular nucleus. Our results suggested that peanut shell extract have a strong renal protective effect against glycerol-induced ARF. - - NO-dependent neural pathway in the hypothalamic paraventricular nucleus may be part of possible mechanism of renal protection.