| Objective:Diabetic kidney disease(DKD)is the main microvascular complication of diabetes.DKD has become the first cause of end-stage renal disease(ESRD)in the world.The main purpose of this study is to explore the effect,safety and related mechanism of integrated Traditional Chinese and Western medicine in improving DKD microvascular function.Methods:This study is divided into four parts.The first part is network pharmacology study:the mechanism of Shenkang injection in treating DKD is systematically explored through network pharmacology.Main active components and corresponding targets of Shenkang injection were screened by TCMSP platform.Related targets of DKD were screened by Genecards database to obtain disease-drug intersection targets.According to the method of bioinformatics,the functional enrichment analysis of Gene ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis of Shenkang injection for the treatment of DKD are performed,and use molecular docking to verify.The second part is evidence-based medicine research:online retrieval of major Chinese and English databases,including CNKI,Wanfang Database,VIP Database,China Biomedical Literature Database,The Cochrane Library,Medline,EMBase and Web of Science,randomized controlled trials(RCTs)of Shenkang injection combined with alprostadil and alprostadil alone in the treatment of DKD are screened.Scr,24 hour urine protein quantitative(24h UTP)and other indicators are used to meta-analysis.The third part is the clinical efficacy observation study of Shenkang injection combined with alprostadil in the treatment of elderly patients with diabetic nephropathy and non-diabetic nephropathy(CKD3-4):elderly CKD3-4 patients hospitalized in our hospital in recent 10 years were divided into DKD and non-DKD groups,and divided into control group,Shenkang injection group,alprostadil group and Shenkang injection combined with alprostadil group according to the medication situation,and the improvement of renal function and urinary protein of patients before and after treatment are analyzed.The fourth part is the preliminary study of Shenkang injection improving the microvascular function of diabetic nephropathy model mice(db/db mice):The expression of Scr,urinary protein and CD34 in renal vascular endothelial cells of normal control mice(m/m mice),DKD model mice(db/db mice)and model plus Shenkang treated mice after 4,8 and 12 weeks of treatment were compared.To investigate the effect of Shenkang injection on DKD microvascular function and renal function.Results:Part 1 is network pharmacology:120 Shenkang injection active components,1948 corresponding targets and 4444 DKD related targets are obtained,so 183 disease-drug intersection targets were obtained and 59 DKD related pathways were involved in Shenkang injection treatment.Through molecular docking results:Worenine,Berlambine and Mitogen-activated protein kinase 8(MAPK8),the active components of Shenkang injection were screened.MAPK8,JUN,APP and other potential targets have good binding ability.Through network pharmacology study,it was found that the active components of Shenkang injection can improve renal function and reduce urinary protein by regulating immune inflammatory response,energy metabolism,autophagy and other pathways,thus delaying the progression of DKD.Part 2 is meta-analysis:observation group is superior to control group in reducing 24h UTP(MD:-0.22,95%IC[-0.44,-0.01]).The observation group also has better efficacy in reducing Scr and blood urea nitrogen(BUN)(Scr MD:-11.87,95%IC[-13.11,-10.63];95%IC[-2.44,-1.78]).Subgroup analysis showes that with the increase of the original base value of Scr and BUN,the advantage of Scr and BUN decreased more significantly in the observation group,in general.We find that Shenkang injection combined with alprostadil is superior to alprostadil alone in the treatment of diabetic nephropathy,and the effect is more significant when renal function is poor.Part 3 is clinical study:A total of 754 patients are enrolled,in which 239 patients are in the control group,240 patients are in the Shenkang group,142 patients are in the alprostadil group and 133 patients are in the combined group.There are no significant differences in sex,age,blood pressure,24h UTP,serum albumin,glomerular filtration rate,Scr and BUN in the four groups before treatment(P>0.05).The treatment period of the four groups are 9.5-12 days.After treatment,Scr in control group is not significantly improved compared with before(P>0.05),and Scr in Shenkang group,alprostadil group and combined group is decreased compared with before(P<0.05).In terms of 24h UTP,Shenkang group,alprostadil group and combination group decrease compared with before treatment(P<0.05):In serum albumin,except for the combination group,there is no significant difference in the other three groups compared with before treatment(P>0.05).Through subgroup analysis,we find that Shenkang group,alprostadil group and combined group have better efficacy than DKD patients,and could effectively improve the renal function of NDRD patients.For DKD patients,although there is no statistical difference in renal function improvement between the three treatment groups before and after treatment(P>0.05),Scr decrease to a certain extent,which is significantly improved compared with DKD patients in the control group(P<0.05).We also find that patients with stage 4 CKD have better renal function improvement before and after treatment than patients with stage 3 CKD.In terms of safety,none of the four groups show significant adverse reactions during treatment.Part 4 is animal experiment:After 12 weeks of shenkang injection treatment,urine protein and Scr of mice in the model plus Shenkang treatment group are significantly lower than those in the model control group.At the same time,Shenkang injection can increase the expression of local CD34 protein in kidney to some extent by renal pathological manifestations,indicating that Shenkang injection may improve local circulation of kidney by alleviating renal microvascular endothelial injury.Conclusions:The active ingredients of Shenkang injection have multiple targets,multiple pathways and can comprehensively regulate immune inflammatory response,energy metabolism and autophagy,improve renal function and reduce urinary protein,thus delaying the progression of DKD.Shenkang injection combined with alprostadil is better than alprostadil alone in the treatment of DKD,and the effect is more significant when renal function is poor.In the treatment of elderly patients with DKD and NDRD,Shenkang injection,alprostadil and combined treatment group could improve renal function and reduce urinary protein,and the effect was significantly better than the control group(P<0.05),but the effect of NDRD patients was better than DKD patients.Preliminary animal studies suggest that Shenkang injection therapy may improve local renal circulation by alleviating renal microvascular endothelial injury. |
