Atractylenolide ? Protects Cardiac And Renal Function Of Rats With Cardiorenal Syndrome Via Suppressing Fibrosis Synthesis

Background:The interaction between the heart and kidney,where functional lesion of either organ will result in the impairment of another one,is known as 'cardiorenal syndrome'.At this stage,the modeling of permanent coronary artery ligation combined with nephrectomy is commonly employed in animal experiments,since it can better simulate clinical conditions of cardiorenal syndrome.Cardiac and renal fibrosis,whose pathogenesis was closely related to inflammation,were proved to be important pathological features of cardiorenal syndrome.Experiments also showed that Atractylenolide I could reduce proliferation of endothelial cells by inhibiting the activation of inflammatory cytokines.However,up till now,no report has been made on the anti-fibrosis of the heart and kidney in Atractylenolide I.Therefore,in this research,the modeling of permanent coronary artery ligation combined with 3/4 nephrectomy was used,aiming at exploring whether Atractylenolide I could inhibit cardiac and renal fibrosis of the rats with cardiorenal syndrome and as well protect their cardiac and renal function.Objective:This research aimed at exploring whether Atractylenolide I could protect cardiac and renal function with its anti-fibrosis effect,employing the new SD rat model improved from the current models of cardiorenal syndrome.Methods:In order to establish new CRS model,twenty SD rats were randomly categorized into Sham group(7 rats)and Model group(13 rats).In Model group,the rats were permanently ligated of coronary artery,after 1 week,had 3/4 subtotal nephrectomy.Other than the ligation of artery and the resection of kidney,the operation of the rats in Sham group were the same as that of Model group.The rats were subjected to ECG immediately after the coronary artery ligation,while Scr,BUN,24h urinary protein,Ucr,BNP and cardiac ultrasonography were measured at the subsequent 2nd and 4th week.The measurement of creatinine clearance followed.Besides,heart and kidney tissues were stained in three different ways:HE staining,Masson staining and Immunofluorescence staining of TGF-?1 Collagen ?/? and ?-SMA sections.Results showed that,with the advantages of high stability,good reproducibility and short experimental cycle,the new rat model of cardiorenal syndrome was suitable for the study of pathogenesis and pharmacological effects of cardiorenal syndrome.The above-mentioned model was applied to fifty SD rats.One week after nephrectomy,42 surviving rats were subjected to echocardiography and 5 rats(LVEF>60%)were removed.The remaining 37 rats were then randomly divided into Model group(n = 10),Low-dose group(n = 9),Middle-dose group(n = 9)and High-dose group(n = 9).In Model group,the rats were intraperitoneal injected with normal saline,while in the rats in Low-dose group(0.3mg/kg),Middle-dose group(lmg/kg)and High-dose group(3mg/kg)were intraperitoneal injected with Atractylenolide I.Scr,BUN,24h urinary protein,BNP and echocardiography were measured after 2 weeks,moreover,heart and kidney tissues were stained in three different ways:HE staining,Masson staining and Immunofluorescence staining of TGF-?1,Collagen I and a-SMA sections.Results:1.Biochemical indicators showed that,compared to Model group,the renal function of rats in Low-dose,Medium-dose and High-dose groups were significantly improved(P<0.05).The levels of BNP in Medium-dose and High-dose groups were significantly lower than that of Model group(P<0.05).2.In comparison to Model group,the heart mass index and left ventricular mass index decreased in Low-dose,Medium-dose and High-dose groups,especially in High-dose group(P<0.05).The kidney mass index decreased significantly in the three medicated groups(P<0.05).3.Results of echocardiography revealed that the levels of CO,SV,LVEF,LVFS,LVAWs and LVAWd were significantly higher in in Low-dose,Medium-dose and High-dose groups(P<0.05).4.In the three medicated groups,HE staining showed that the infiltration of inflammatory cells in the non-infarcted area of heart and kidney was reduced,additionally,Masson staining revealed that the ratio of fiber area in the non-infarcted area of heart and kidney were significantly reduced in a dose-dependent manner(P<0.05).5.In medicated groups,the fluorescence intensity of TGF-?1,collagen I,a-SMA in the non-infarcted area of heart and kidney were significantly lower than those of Model group(P<0.05),as well,in a dose-dependent manner.Conclusion:In a dose-dependent manner,Atractylenolide I can inhibit cardiac and renal fibrosis of rats with cardiorenal syndrome,simultaneously,protect their cardiac and renal function.The anti-fibrosis effects of Atractylenolide I may be related to the inhibition of TGF-?1 expression,and the formation of collagen I and a-SMA in cardiac and renal tissues..