肾消通络方通过PGC-1α调控代谢重编程和线粒体动力学减轻糖尿病小鼠心肌损伤和肾损伤OA

AIM:To explore the protective effects of the Shenxiao-Tongluo formula(SXTL)on myocardial and renal tissues in diabetic mice and its influence on peroxisome proliferators-activated receptor γ coactivator-1α(PGC-1α)-mediated metabolic reprogramming and mitochondrial dynamics based on the theory of blood stasis in collaterals.METHODS:Forty-three CD-1 mice were randomly divided into a normal group with 10 mice and a modeling group with 33 mice.The modeling group were intraperitoneally injected with streptozotocin to establish a diabetic animal model.The successfully modeled mice were randomly divided into a model group,an empagliflozin treatment group,and a SXTL group,with 10 mice in each group.They were treated with the corresponding drugs for 8 weeks.The levels of 24-hour urine total protein(24 h UTP),cardiac troponin T(cTnT),lactate dehydrogenase A(LDHA)and creatine kinase-MB(CK-MB)were detected by ELISA.The levels of blood urea nitrogen(BUN)and serum creatinine(SCr)were determined by an automatic biochemical analyzer.Hematoxylin-eosin(HE)and Masson staining was used to detect pathological changes in the heart and kidney.Immunohistochemistry was used to detect the protein expression of ATP synthase subunit beta(ATP5b),pyruvate kinase M2(PKM2),dynamin-related protein 1(Drp1)and optic atrophy 1(OPA1)in the heart and kidney tissues.Western blot was used to detect the protein expression of PGC-1α,ATP5b,cytochrome C oxidase sub-unit 6c(Cox6c),PKM2,LDHA,Drp1,fission 1(FIS1),OPA1 and mitofusin 2(Mfn2)in the heart and kidney tissues.RESULTS:Compared with the normal group,the levels of 24 h UTP,BUN,SCr,cTnT,CK-MB and LDHA in the model group were significantly increased(P<0.01).Mocardial cells were arranged disorderly,and the blue-stained collagen fi-bers in the myocardium increased.Glomerular hypertrophy,mesangial hyperplasia,and collagen fiber deposition in the renal interstitium were detected.The protein levels of mitochondrial fusion(OPA1 and Mfn2),oxidative phosphorylation(ATP5b and Cox6c)and regulatory factor(PGC-1α)in myocardial tissues and renal tissues were decreased(P<0.01),and the protein levels of mitochondrial division(Drp1 and FIS1)and glycolysis(PKM2 and LDHA)were increased(P<0.05).Compared with the model group,the pathological damage and functional impairment of the heart and kidney in the mice of each drug administration group were attenuated,and the disorders of mitochondrial dynamics and metabolic repro-gramming in myocardial and renal tissues were also alleviated.CONCLUSION:Treatment with SXTL can significantly attenuate myocardial injury and renal injury in diabetic mice.The mechanism may be attributed to regulating metabolic re-programming and mitochondrial dynamics balance via PGC-1α,thereby attenuating mitochondrial damage.