Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan, ROC.
Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan, ROC; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 83301, Taiwan, ROC.
Biomed Pharmacother. 2019 Aug;116:108954. doi: 10.1016/j.biopha.2019.108954. Epub 2019 May 17.
This study tested the hypothesis that Entresto could safely and effectively preserve heart and kidney function in rats with cardiorenal syndrome (CRS) induced by 5/6 nephrectomy and intra-peritoneal doxorubicin administration (accumulated dosage up to 7.5 mg/kg) together with daily high-protein-diet (H).
Adult male Sprague-Dawley rats (n = 24) were equally categorized into Group 1 (sham-operated control + H), Group 2 (CRS + H) and Group 3 [CRS + H + Entresto (100 mg/kg/day orally) since Day 14 after CRS induction] and euthanized by Day 63 after CRS induction. By Day 63, circulatory BUN and creatinine levels and ratios of urine protein to creatinine were significantly higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, whereas left-ventricular ejection fraction and kidney weight showed an opposite pattern among all groups (all p < 0.001). Microscopically, fibrosis area and intensity of oxidative stress (i.e., DCFDA stain) in kidney/heart tissues exhibited a pattern identical to that of creatinine level among all groups (all p < 0.0001). Kidney injury score and protein expressions of autophagy (i.e., beclin-1/Atg-5/protein ratio of LC3-BII/LC3-BI), fibrosis (Smad3/TGF-ß), apoptosis (mitochondrial-Bax/capase2/3/9), oxidative-stress (NOX-4/oxidized protein/xanthine-oxidase/catalase), membranous p47phox phosphorylation and mitochondrial-damage biomarker (cytosolic-cytochrome-C) were higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, while protein expressions of anti-apoptosis (Bcl-2/Bcl-XL) and mitochondrial integrity (mitochondrial-cytochrome-C) markers displayed an opposite pattern among all groups in kidney tissues (all p < 0.0001).
Oral administration of entresto was safe and could offer protection against CRS-induced heart and kidney damage.
本研究旨在检验依那普利能否安全有效地保护 5/6 肾切除和腹腔内阿霉素给药（累积剂量达 7.5mg/kg）联合高蛋白质饮食（H）诱导的大鼠心肾综合征（CRS）模型的心肾功能。
成年雄性 Sprague-Dawley 大鼠（n=24）等分为三组：第 1 组（假手术对照+H）、第 2 组（CRS+H）和第 3 组[CRS+H+依那普利（100mg/kg/天，口服，从 CRS 诱导后第 14 天开始]，并于 CRS 诱导后第 63 天安乐死。第 63 天，第 2 组循环血 BUN 和肌酐水平以及尿蛋白与肌酐比值均明显高于第 1 组和第 3 组，第 3 组又明显高于第 1 组，而左心室射血分数和肾脏重量在各组之间呈相反模式（均 p<0.001）。显微镜下，各组肾/心组织纤维化面积和氧化应激强度（即 DCFDA 染色）与肌酐水平呈相同模式（均 p<0.0001）。肾损伤评分和自噬（即 beclin-1/Atg-5/LC3-BII/LC3-BI 蛋白比）、纤维化（Smad3/TGF-β）、凋亡（线粒体-Bax/caspase2/3/9）、氧化应激（NOX-4/氧化蛋白/黄嘌呤氧化酶/过氧化氢酶）、膜 p47phox 磷酸化和线粒体损伤生物标志物（胞质细胞色素 C）在第 2 组中的表达均高于第 1 组和第 3 组，且第 3 组又明显高于第 1 组，而肾组织中抗凋亡（Bcl-2/Bcl-XL）和线粒体完整性（线粒体细胞色素 C）标志物的蛋白表达则呈相反模式（均 p<0.0001）。
依那普利口服给药安全，并能预防 CRS 引起的心脏和肾脏损伤。
