Analyzing The Compatibility Law Of Core Chinese Medicine For Hypertensive Renal Damage Based On Real-World Data And Its Renal Protective Mechanism Research

Objective:Analyzing the compatibility law of core Chinese medicines(Gao Shen Formula: Salvia miltiorrhiza,Angelica sinensis,Codonopsis pilosula,Rhizoma atractylodes,Pinellia ternata,Rhizoma curcumae and Licorice)for hypertensive renal damage based on real-world data;And through animal experiments,based on 4D Label Free proteomics technology to analyze the mechanism of action of renal protection.Methods:1.Drug compatibility analysis: the case data of 2055 confirmed hypertensive renal damage patients in the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from July 1,2014 to May 31,2017 were collected,the distribution of syndrome elements in hypertensive renal damage patients was analyzed by syndrome elements extraction,the Apriori algorithm was used to analyze the compatibility association between drugs,and the relationship between drug compatibility was analyzed from the dose perspective by constructing a Copula function model.2.Proteomic analysis: Spontaneously Hypertensive Rats(SHR)were used as a model,Wistar Kyoto(WKY)rats were used as controls,and were divided into Gao Shen Formula(GSF group),model group(Model group)and control group(Con group);Eight weeks after the drug intervention,each group randomly selected 3 renal parenchymal tissue samples for 4D Label Free proteomic analysis,and the mechanism of Gao Shen Formula exerting renal protection was explored according to the proteomic results.Results:1.The distribution of hypertensive renal damage syndrome elements,qi deficiency,sputum turbidity and blood stasis accounted for the top three,accounting for 63.21%,43.41% and 32.85%,respectively.There were 1003 cases of qi deficiency and phlegm turbidity,qi deficiency and blood stasis and blood stasis and sputum turbidity,accounting for 48.81%;It can be seen that qi deficiency,phlegm turbidity and blood stasis are the key syndrome elements in the pathogenesis of hypertensive renal damage.The seven drugs in Gao Shen Formula can correspond to the three major syndrome elements of qi deficiency,phlegm turbidity and blood stasis in hypertensive renal damage,and from the perspective of syndrome elements,we further explain the rationality of Gao Shen Formula as the core prescription for the treatment of hypertensive renal damage.The analysis results of Apriori algorithm showed that three groups of drug pairs with significant correlation were obtained in Gao Shen Formula,namely Rhizoma atractylodes and Codonopsis pilosula,Rhizoma atractylodes and Pinellia ternata and Salvia miltiorrhiza and Angelica sinensis.The Copula function model showed that there was a very robust nonlinear positive correlation between the doses of Rhizoma atractylodes and Codonopsis pilosula under syndrome elements of qi deficiency,and the doses of Rhizoma atractylodes and Pinellia ternata under syndrome elements of sputum turbidity,while there was no significant synergistic relationship between the doses of Salvia miltiorrhiza and Angelica sinensis under syndrome elements of blood stasis.2.The results of proteomic analysis showed that a total of 442 upregulated differentially expressed proteins and 522 down-regulated differentially expressed proteins were identified between the Model/Con groups.A total of 228 up-regulated differentially expressed proteins and250 down-regulated differentially expressed proteins were identified between the GSF/Model groups.By obtaining the intersection of the reverseexpressed proteins,we obtained 47 up-regulated intersection proteins and91 down-regulated intersection proteins.By analyzing significantly differentially expressed proteins,we obtained two Gao Shen Formula targeted proteins(Clcnka and Uchl1);Through functional enrichment analysis,we obtained one Gao Shen Formula targeted signaling pathway(complement and coagulation cascade signaling pathway).Conclusion:The study of the distribution of syndrome elements in hypertensive renal damage revealed the rationality of Gao Shen Formula;The drug dose compatibility study laid a foundation for the study of Gao Shen Formula dose optimization and dose-response relationship;From the perspective of“Disease-Syndrome Elements-Drug Pair-Dose”,the application of Copula function in the field of Traditional Chinese Medicine is further enriched,and an alternative method is provided for the improvement of the dosage theory of Traditional Chinese Medicine.Proteomic analysis showed that Gao Shen Formula may exert renal protection against hypertensive renal damage by inhibiting the expression of Clcnka and Uchl1 proteins and inhibiting complement and coagulation cascade signaling pathways.