In conclusion, we have provided evidence demonstrating that pretreatment with GSPE can provide protection against IR-induced acute renal injury by inhibiting the HMGB1-TLR4-P65 pathway and the downstream inflammatory reaction and that consecutively treatment with GSPE after I/R can reduce tubulointerstitial inflammation; thus, renal fibrosis was also decreased. Here, TLR4 is linked to renal fibrosis.