Protective Effect Of Resveratrol On The Acute Kidney Injury In Septic Rats And Its Mechanism

Sepsis complicated with acute kidney injury(AKI) is one of the most important reasons of the high mortality in sepsis. Increased release of various inflammatory cytokines and local inflammation in kidney play important roles in the development of AKI. Nuclear transcription factors Kb(NF-κB) was the key transcriptional regulatory factor of genes related to inflammation, which can induce the transcription of various inflammatory cytokines after being activated. It has been reported that endoplasmic reticulum stress(ERS) mediates the activation of NF-kB inflammatory signaling. Resveratrol is a kind of polyphenolic substance with strong anti-inflammation activity which is closely related to the inhibition of NF-κB activity. However, it is not well known that whether its anti-inflammatory effect is associated with the inhibition of ERS. This research was designed to investigate the protective effect of resveratrol on the acute kidney injury in sepsis and its mechanism.Firstly, a rat model of sepsis was established by cecal ligation and puncture(CLP).108male SD rats were randomly divided into4groups:(1) sham-operated control group(Sham);(2)sham-operated group with30mg/kg resveratrol(Sham+Res);(3)CLP group(CLP);(4)CLP group with30mg/kg resveratrol(CLP+Res). Resveratrol was administrated immediately after CLP operation through intraperitoneal injection. The main parameters were collected during the whole duration and listed as follows:the survival percentage, morphological changes of kidney, serum contents of creatinine(Cr), urea nitrogen(BUN) and inflammatory mediators(TNF-α, IL-1β,IL-6and IL-10), expression of GRP78/BiP, IRE-1, p65and inflammatory mediators(TNF-α, IL-1β, IL-6and IL-10) in kidney.Main results of our study are as follows: (1)Compared with the sham group, the mortality of the CLP group was markedly increased and reached to about60%, and resveratrol significantly reduced the mortality to35%.(2)At12h after operation, compared with the sham group, the serum content of BUN and Cr were markedly elevated in CLP rats, but resveratrol reduced their seurm concentrations with no significant effect on the sham operated rats(P<0.05).Although there was no obvious change in the kidney morphology among all rats, renal tubules was swelled and the lumen was slightly narrowed in CLP rats, and resveratrol restored this changes.(3)At12h after operation, resveratrol significantly reduced the upregulation of BiP, phosphorylated IRE-1and p65expression in the kidney of CLP rats, and p65mainly located in the cytoplasm.(4)At6,12h after operation, resveratrol markedly decreased the upregulation of TNF-a, IL-1β, and IL-6mRNA expression in the kidney of CLP rats(P<0.05). However, no significant effect of resveratrol was found in the IL-10mRNA expression(P>0.05).(5)At6h after operation, resveratrol significantly lower the upregulation of serum TNF-a, IL-1β, and IL-6content(P<0.05), but it had no effect on serum IL-10content(P>0.05). At12h after operation, resveratrol hadn’t only significantly lower the upregulation of serum TNF-α, IL-1β, and IL-6content(P<0.05), but also increase the serum IL-10content(P<0.05).These findings suggest that resveratrol can decrease the mortality of septic rats, protect the AKI induced by sepsis; the relief of ERS, inhibition of NF-κB activation and reduction of inflammation response in the kidney may be all involved in this process.