Protective Effect And Mechanism Of Rosiglitazone On Lipopolysaccharide-induced Acute Renal Injury

Multiple organ dysfunction syndrome caused by septic shock and sepsis is a common problem in clinical patients.Sepsis still has a high mortality rate,despite advances in anti-infective treatment.Acute kidney injury(AKI)is a common clinical syndrome characterized by rapid decline in renal function caused by a variety of etiologies and pathological mechanisms.Epidemiological studies have shown that the mortality rate of AKI in clinical intensive care patients is as high as 70%,while 46%~48% of AKI is caused by sepsis.AKI is a common clinical critical disease,and sepsis caused by bacterial lipopolysaccharide(LPS)is a common cause of AKI,with a high fatality rate.Its pathological changes may be related to LPS-induced inflammation and oxidative stress,and currently there is no ideal prevention and treatment.Peroxisome proliferator-activated receptor gamma(PPAR?)belongs to the nuclear receptor superfamily and is a ligand-dependent nuclear receptor transcription factor.Rosiglitazone(RSG)is a synthetic PPAR? ligand,which plays a role by activating the transcription level of PPAR? to regulate the downstream target genes.Recent studies have shown that PPAR? has anti-inflammatory and inhibitory effects on oxidative stress,but it is unclear whether RSG can combat LPS-induced renal inflammation and oxidative stress to reduce acute kidney injury.In this study,the protective effect of RSG on LPS-induced acute renal injury with mice was studied and the possible protective mechanism was discussed from the perspective of anti-inflammatory and oxidative stress inhibition.Objective:The protective effect of PPAR? aganist RSG on LPS-induced acute kidney injury in mice should be clarified,revealing the mechanism of its protective effect on LPS-induced acute kidney injury from anti-inflammatory effect and inhibition of oxidative stress.Methods: 1.Thirty-two male ICR mice were randomly divided into four groups: Control group,RSG group,LPS group,RSG+LPS group.In LPS group,mice were intraperitoneally injected with LPS(2 mg/kg).In RSG+LPS group,mice were pretreated with RSG(10 mg/kg)72,48,24 and 1 h before LPS injection.All mice were sacrificed 6 h after LPS injection.Kidneys and sera were collected.Some kidneys were used for HE staining.Serum inflammatory cytokines were detected by ELISA.The expressions of renal inflammatory cytokines were analyzed using RT-PCR.Renal NF-?B p65 phosphorylation was measured through Western blotting.2.Forty-eight male ICR mice were divided into six groups: Control group,RSG group,LPS 6h group,LPS 24 h group,RSG+LPS 6 h group,RSG+LPS 24 h group.In the LPS and LPS+RSG groups,mice were intraperitoneal injected with LPS(2 mg/kg).In the RSG and RSG+LPS groups,mice were administered with RSG(10 mg/kg)by gavage four consecutive days before LPS injection.All mice were sacrificed at 6 h and 24 h after LPS injection.Some kidneys were collected for HE staining.Renal GSH and MDA were detected using biochemical method.Renal oxidant stress related genes were analyzed through real time RT-PCR.Renal NADPH oxidase-2 and NOX-4 were measured by Western blotting.Serum was acquired for renal function.Results: 1.RSG pretreatment ameliorated LPS-induced acute kidney injury and inflammatory cell infiltration.Moreover,RSG pretreatment inhibited LPS-induced elevation of serum inflammatory cytokines.In addition,RSG pretreatment alleviated LPS-induced upregulation of proinflammatory cytokines and chemokines.Finally,RSG pretreatment suppressed LPS-induced renal NF-?B p65 phosphorylation.2.LPS-induced AKI,as determined renal pathological damage and renal function injury,was attenuated in RSG-pretreated mice.Although it did not affect renal GSH level,RSGpretreatment evidently inhibited the elevation of renal MDA content.Mechanistically,RSG pretreatment distinctly repressed LPS-induced upregulation of P47 phox m RNA and nicotinamide adenine dinucleotide phosphate(NADPH)oxidase(NOX)-2 and NOX-4 in the kidney.Conclusion: 1.Rosiglitazone has protective effect on acute renal injury induced by LPS.2.Rosiglitazone's protective effect on LPS-induced acute renal injury is related to anti-inflammatory and inhibition of renal oxidative stress.