Exploration The Correlation Of Chronic Heart Failure With Kidney Fibrosis And The Interventional Effect Of Danshen-Chuanxiong Injection Based On “Causal Chains From Heart^TM To Kidney^TM”

Cardiorenal disease caused by chronic heart failure is one of the major medical problems in the context of global population ageing.In the field of modern medicine,much progress has been made in exploring the multiple interactions between heart and kidney,such as hemodynamics,neuroendocrine,immunity and so on.However,there is no ideal treatment option for how to regulate the"complex giant system"of heart-kidney interactions.Traditional Chinese medical theory holds that,in the human internal system,the heart ^TMacts as the"great governor of five zang-organs and six fu-organs","The pathogenesis of heart ^TMwill be transmitted to the other four zang-organs,among which"Causal chains from Heart ^TMto Kidney ^TM"is vatal.Promoting blood circulation to remove blood stasis method is the key treatment for diseases related to"Causal chains from Heart ^TMto Kidney ^TM",and is used in combination with other treatments such as Wenyang,Yiqi,Lishui methods in the practice of traditional medicine.Hence,the authors speculate that there may be clues to discover mechanisms and innovative drugs that can regulate both heart failure and kidney injury in the process of activating blood circulation and resolving blood stasis in Chinese medicine to regulate"Causal chains from Heart ^TMto Kidney ^TM"-related diseases.In this paper,a model of Transverse Aortic Constriction was established to determine the time cycle from renal injury to fibrosis,and the clinically effective Guanxinning injection（GXN）was used as a representative test drug to drug pair of Danshen-Chuanxiong.The correlation between chronic heart failure and renal fibrosis and the interventional effect of Danshen-Chuanxiong injection were studied using methods from proteomics,metabolomics,network pharmacology and molecular biology.The full text was divided into six chapters.The main contributions of the author were as follows:1.A mouse model of Transverse Aortic Constriction causing chronic heart failure with renal injury was established,the cycle of dramatic progression of renal fibrosis was determined to be 12-16 weeks after surgery,and the model can be used in studies related to the intervention of Danshen-Chuanxiong injection in renal fibrosis caused by heart failure.2.Molecular mechanisms including energy metabolism,oxidative stress,inflammation,immune regulation and hormone synthesis were found to be involved in renal fibrosis induced by chronic heart failure.3.The interventional effect and metabolic mechanisms of Danshen-Chuanxiong injection in the process of renal fibrosis caused by chronic heart failure was investigated.The results showed that Danshen-Chuanxiong injection could significantly maintain the contractile function,delay the ventricular remodeling,improve the renal function,alleviate the renal pathological damage and fibrosis to a certain extent in heart failure mice;the protective effect was found to be related to regulation of redox and energy metabolism in vivo,involving aspartate metabolism,homocysteine degradation,glycine and serine metabolism,etc.4.Network analysis combining the results of proteomic and metabolomic analysis revealed that the intervention of Danshen-Chuanxiong injection may be related to the regulation of excessive oxidative stress in the kidney,the regulation of neurotransmitter synthesis such as catecholamines,and the regulation of inflammatory processes.Quantitative protein analysis showed that the regulation of excessive oxidative stress in the kidney by Danshen-Chuanxiong injection was associated with up regulation of CAT,ferroptosis-related proteins GPX4,FTH1 and HO-1,down regulation of GSS,inhibition of XOD and NOS,and ferroptosis in kidney cells.5.The chemical composition analysis and network pharmacology analysis results predicted that the main active ingredients related to Danshen-Chuanxiong injection in the intervention process of renal fibrosis caused by chronic heart failure may included rosmarinic acid,caffeic acid,protocatechuic acid,ferulic acid,protocatechuic aldehyde,salvinorin,salvianolic acid A,isoleucine,chuanxiong lactone E,chuanxiong lactone G,etc.6.Thirty-five new metabolites（potential effector response substances）associated with Danshen-Chuanxiong injection in the renal fibrosis process induced by chronic heart failure were obtained by multivariate statistical analysis,in which 16 new metabolites were found to be related with phenylpyruvate and 25 related with riboflavin.