The Role Of TNF-α Signaling Pathway In The Development Of "nephrogenous Cardiac Sympathetic Nerve Remodeling"

Objectives: The present study was aimed to explore the mechanism of tumor necrosis factor(TNF-α)signaling pathway in cardiac sympathetic remodeling induced by chronic renal failure(CRF)model in rats.Methods: 1.A rat CRF model was established by the 5/6 nephrectomy.Forty-eight wistar rats were randomly divided into 4 groups(n=12): sham operation group(Sham group),CRF group,CRF+atorvastatin group(CRF+statin group),CRF+etanercept group(CRF+ Rh TNFR: Fc group).Since 4 days after the surgery,rats in CRF+statin group were given atorvastatin 5mg/Kg daily by intragastric administration for 8 weeks.Rats in CRF+Rh TNFR:Fc group were given etanercept 0.4mg/Kg twice a week by subcutaneous injection for 8 weeks.2.All rats were sacrificed 8 weeks after surgery.The apex and bottom of ventricle myocardial tissue were retained for western-blotting.The rest part of myocardial tissues were used for HE,immunofluorescence staining and masson staining.In vivo ventricular electrophysiological experiments were performed at 8 weeks after surgery to detect the ventricular effective refractory period(VERP)and ventricular fibrillation threshold(VFT).Results: 1.Overall condition: The body weight of rats after nephrectomy significantly decreased compared to Sham group(P<0.05).The serum creatinine values of rats in CRF group,CRF+statin group and CRF+Rh TNFR:Fc group were significantly increased at 2 weeks,6 weeks,and 8 weeks as compared with Sham group(P<0.05).2.Echocardiographic results: The left ventricular end-diastolic diameter and ratio of ventricular/body weight of rats in CRF group,CRF+statin group and CRF+Rh TNFR: Fc group were significantly increased compared to Sham group(P<0.05),while the ratio of ventricular/body weight of rats in CRF+statin group and CRF+ Rh TNFR:Fc group were decreased compared to CRF group(P<0.05).3.Masson staining results: Myocardial fibrosis was more obvious in CRF group compared to that in Sham group.While the intervention of etanercept and atorvastatin could alleviate myocardial fibrosis to a certain extent.4.Immunofluorescence staining results: The GAP-43 and TH positive area fraction of rats in CRF group increased significantly compared to Sham group(P<0.05),while the GAP-43 and TH positive area fractions in CRF+Rh TNFR:Fc group and CRF+ statin group were lower than were those in CRF group(P <0.05).5.ELISA results: The concentrations of TNF-α and IL-1β in CRF group were significantly higher than those in Sham group(P <0.05),while the concentrations of above variables in CRF+statin group and CRF+Rh TNFR:Fc group were significantly lower than were those in CRF group(P <0.05).6.Western-blotting results: The expression levels of GAP-43,NGF and TNF-α in CRF group were higher than Sham group(P <0.05),while above variables were lower in CRF+Rh TNFR:Fc group and CRF+statin group than CRF group(P <0.05).7.In vivo ventricular electrophysiological results: There was no significant difference in VERP between the four groups.However,VFTs in CRF group were significantly lower than were those in Sham group(P <0.05),while VFTs in CRF+ Rh TNFR:Fc group and CRF+statin group were higher than CRF group(P <0.05).Conclusions: 1.The present study suggested that CRF would result in cardiac sympathetic never remodeling,left ventricular remodeling and triggering ventricular arrhythmia.2.The concentrations of TNF-α and the expression levels of NGF were decreased in the rats receiving etanercept treatment.Moreover,cardiac sympathetic remodeling and myocardial remodeling were significantly alleviated after etanercept treatment,suggesting the inflammatory mechanisms might play an important role in the development of cardiac sympathetic never remodeling in rats with CRF.3.CRF Rats receiving atorvastatin treatment showed improved cardiac sympathetic nerve remodeling and higher VFT,suggesting atorvastatin might have a role in the treatment of CRF associated ventrricular arrhythmias.