*Purpose: Cordycepin (3’-deoxyadenosine) is a naturally occurring adenosine analogue and onem of the bioactive constituents isolated from Cordyceps militaris/Cordyceps sinensis, species of the fungal genus Cordyceps. It has traditionally been a prized Chinese folk medicine for the human well-being. However, the actions of cordycepin against renal ischemia/ reperfusion injury (I/R) are still unknown. In the present study, rats were subjected to I/R and cordycepin was intragastrically administered for seven consecutive days before surgery to investigate the effects and mechanisms of cordycepin against renal I/R injury.

*Methods: Cordycepin treatment in rats was conducted by oral gavage for 7 consecutive days before the I/R surgery. The renal and blood samples were harvested at 24 h after reperfusion. Hematoxylin and eosin staining (H & E) of representative renal sections, Paller scores for the histological appearance of acute kidney necrosis. Circulating levels of BUN and Cr in each experimental group.The expression of pro-inflammatory factors (IL-1b, IL-6, TNF-a) in renal tissuewere measured by real-time PCR. Detection of MyD88/TLR4 protein expression in renal tissue by western blot analysis reflected the intensity of inflammation laterally. Quantitative analyses of the expression of TLR4 and MyD88 proteins by comparing the gray scale value.

*Results: The results show that cordycepin can significantly decrease the degree of enhancement in the BUN level and Cr level in the blood. the transcription levelsof the common pro-inflammatory cytokines, including IL-1β, IL-6 and TNF-a, toreflect the degree of inflammation in kidney tissue. Cordycepin significantly affected the mRNA expressions of these cytokines, Qualitative and semi-quantitative experiments using western blot analysis showed that cordycepin could significantly decrease the expressions of TLR4 and MyD88 at protein level. Cordycepin reduced the I/R-induced intensity of TUNEL green fluorescence obviously. We tried to analyze the antioxidant mechanism of cordycepin by measuring the key anti-oxidative stress proteins Nrf2 and HO-1. Western blot analysis showed that cordycepin could increase the expression of these two proteins.

*Conclusions: These data provide new insights for investigating the natural product with the nephroprotective effect against I/R, which should be developed as a new therapeutic agent for the treatment of I/R in the future.

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