The Role Of Histone Deacetylase 3 In Renal Injury Induced By Myocardial Ischemia Reperfusion In Diabetic Rats

Objective:To evaluate the role of histone deacetylase 3(HDAC3)in renal injury induced by myocardial ischemia reperfusion(IR)in diabetic rats and its possible mechanism.Methods:SPF healthy adult male Sprague-Dawley rats,weighing 210-220 g,were used in this study.Diabetes mellitus rats was induced by intraperitoneal injection of l% streptozotocin 60 mg/kg.Eighteen diabetic rats were divided into 3 groups(n=6each)using a random number table method: sham operation group(group S),IR group(group IR)and myocardial IR with HDAC3 inhibitor RGFP966 group(group RG).The myocardial IR model was established by ligation of the left anterior descending coronary artery for 30 min followed by 120 min reperfusion.In the RG group,RGFP966(10mg/kg)was injected intraperitoneally 1h before myocardial IR.The right internal carotid artery was isolated at the end of reperfusion for measurement of serum lactate dehydrogenase(LDH),creatine kinase-MB(CK-MB),creatinine(Cr)and urea nitrogen(BUN).Pathological changes of the kidney were observed under light microscope after HE staining,and evaluated by the scores of renal tubular injury.The apoptosis of renal tissue cells was observed by TUNEL staining,and evaluated by the apoptosis index.The levels of superoxide dismutase(SOD)and malondialdehyde(MDA)in renal tissues were measured by colorimetry.The expression of histone deacetylation 3(HDAC3),silencing regulator 1(SIRT1)and interleukin-1β(IL-1β)in renal tissues were detected by Western blot.Results :(1)Compared with the S group,IR group showed obvious tubules dilation,flat,brush edge damage,with shed and dead cells in the lumen of some tubules in light microscope.Compared with the S group,the renal tubular injury score and apoptosis index were increased(P<0.05);the levels of serum LDH,CK-MB,Cr,BUN were increased;the level of MDA in renal tissues was increased,while the level of SOD was decreased(P<0.05).The expression of HDAC3 and IL-1β were up-regulated and the expression of SIRTl was down-regulated in renal tissues(P<0.05).(2)Compared with IR group,RG group showed less pathologic damage,lower tubular damage score and apoptosis index under light microscope(P<0.05).The serum levels of LDH,CK-MB,Cr,BUN were decreased and the level of MDA in renal tissues was decreased with increased level of SOD(P<0.05).Compared with IR group,the expression of HDAC3 and IL-1β were down-regulated and the expression of SIRTl was up-regulated in renal tissues(P<0.05).Conclusion :(1)Up-regulation of HDAC3 expression can mediate increased myocardial IR-induced renal injury in diabetic rats which is closely related to the increased inflammatory response.(2)By inhibiting the activity of HDAC3,the expression of SIRT1 was up-regulated and the inflammatory response was inhibited,thereby reducing the renal injury induced by myocardial IR in diabetes mellitus.