Atorvastatin,etanercept and the nephrogenic cardiac sym-pathetic remodeling in chronic renal failure rats

Jing-Yue XU; Zheng-Kai XUE; Ya-Ru ZHANG; Xing LIU; Xue ZHANG; Xi YANG; Tong LIU; Kang-Yin CHEN

doi:10.26599/1671-5411.2024.04.007

摘要：BACKGROUND Chronic renal failure(CRF)patients are predisposed to arrhythmias,while the detailed mechanisms are un-clear.We hypothesized the chronic inflammatory state of CRF patients may lead to cardiac sympathetic remodeling,increasing the incidence of ventricular arrhythmia(VA)and sudden cardiac death.And explored the role of atorvastatin and etanercept in this process. METHODS A total of 48 rats were randomly divided into sham operation group(Sham group),CRF group,CRF+atorvastat-in group(CRF+statin group),and CRF+etanercept group(CRF+rhTNFR-Fc group).Sympathetic nerve remodeling was ass-essed by immunofluorescence of growth-associated protein 43(GAP-43)and tyrosine hydroxylase positive area fraction.Electro-physiological testing was performed to assess the incidence of VA by assessing the ventricular effective refractory period and vent-ricular fibrillation threshold.The levels of tumor necrosis factor-alpha(TNF-α)and interleukin-1beta were determined by Western blotting and enzyme-linked immunosorbent assay. RESULTS Echocardiogram showed that compared with the Sham group,left ventricular end-systolic diameter and ventricular weight/body weight ratio were significantly higher in the CRF group.Hematoxylin-eosin and Masson staining indicated that my-ocardial fibers were broken,disordered,and fibrotic in the CRF group.Western blotting,enzyme-linked immunosorbent assay,immunofluorescence and electrophysiological examination suggested that compared with the Sham group,GAP-43 and TNF-α pro-teins were significantly upregulated,GAP-43 and tyrosine hydroxylase positive nerve fiber area was increased,and ventricular fibrillation threshold was significantly decreased in the CRF group.The above effects were inhibited in the CRF+statin group and the CRF+rhTNFR-Fc group. CONCLUSIONS In CRF rats,TNF-α was upregulated,cardiac sympathetic remodeling was more severe,and the nephrogenic cardiac sympathetic remodeling existed.Atorvastatin and etanercept could downregulate the expression of TNF-α or inhibit its ac-tivity,thus inhibited the above effects,and reduced the occurrence of VA and sudden cardiac death.