Division of Nephrology, Zhujiang Hospital, Southern Medical University, Guangzhou 510282, China.
Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515,China.
Eur J Pharmacol. 2017 Jun 5;804:57-67. doi: 10.1016/j.ejphar.2017.03.037. Epub 2017 Mar 18.
Oxidative stress aggravates renal fibrosis, a pathway involved in almost all forms of chronic kidney disease (CKD). However, the underlying mechanism involved in the pathogenesis of renal oxidative stress has not been completely elucidated. In this study, we explored the role and mechanism of hypochlorite-modified albumin (HOCl-alb) in mediating oxidative stress and fibrotic response in a remnant-kidney rat model. Five-sixths nephrectomy (5/6 NX) was performed on the rats and then the animals were randomly assigned to intravenous treatment with either vehicle alone, or HOCl-rat serum albumin (RSA) in the presence or absence of SS-31 (administered intraperitoneally). A sham-operation control group was set up concurrently. Compared with the control group, 5/6 NX animals displayed marked mitochondrial (mt) dysfunction, as evidenced by decrease of mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and manganese superoxide dismutase (MnSOD) activity, release of cytochrome C (Cyto C) from mitochondria to the cytoplasm, and increase of mitochondrial reactive oxygen species in renal tissues. They also displayed increased levels of HOCl-alb in both plasma and renal tissues. These changes were accompanied by accumulation of extracellular matrix, worsened proteinuria, deteriorated renal function, and a marked increase of macrophage infiltration along with up-regulation of monocyte chemoattractant protein (MCP)-1 and transforming growth factor (TGF)-β1 expression. HOCl-alb challenge further exacerbated the above biological effects in 5/6 NX animals, but these adverse effects were prevented by administration of SS-31, a mitochondrial targeted antioxidant peptide. These data suggest that accumulation of HOCl-alb may promote renal inflammation and fibrosis, probably related to mitochondrial oxidative stress and dysfunction and that the mitochondrial targeted peptide SS-31 might be a novel therapy for renal fibrosis and chronic renal failure (CRF).
氧化应激加剧了肾纤维化，这是几乎所有慢性肾脏病（CKD）的发病途径。然而，肾氧化应激发病机制中的潜在机制尚未完全阐明。在这项研究中，我们探讨了次氯酸修饰白蛋白（HOCl-alb）在剩余肾大鼠模型中介导氧化应激和纤维化反应中的作用和机制。对大鼠进行六分之五肾切除术（5/6 NX），然后将动物随机分为静脉注射单独载体组、HOCl-大鼠血清白蛋白（RSA）组以及 HOCl-RSA 加 SS-31 组（腹腔内给药）。同时设立假手术对照组。与对照组相比，5/6 NX 动物表现出明显的线粒体（mt）功能障碍，表现为线粒体膜电位（MMP）、ATP 生成、mtDNA 拷贝数改变和锰超氧化物歧化酶（MnSOD）活性降低，细胞色素 C（Cyto C）从线粒体释放到细胞质，以及肾组织中线粒体活性氧增加。它们还在血浆和肾组织中表现出更高水平的 HOCl-alb。这些变化伴随着细胞外基质的积累、蛋白尿加重、肾功能恶化以及巨噬细胞浸润的明显增加，同时单核细胞趋化蛋白（MCP）-1 和转化生长因子（TGF）-β1 的表达上调。HOCl-alb 挑战进一步加剧了 5/6 NX 动物的上述生物学效应，但这些不良反应可以通过给予线粒体靶向抗氧化肽 SS-31 来预防。这些数据表明，HOCl-alb 的积累可能会促进肾脏炎症和纤维化，可能与线粒体氧化应激和功能障碍有关，而线粒体靶向肽 SS-31 可能是治疗肾纤维化和慢性肾衰竭（CRF）的一种新方法。
