Han Pengxun, Yuan Changjian, Wang Yao, Wang Menghua, Weng Wenci, Zhan Hongyue, Yu Xuewen, Wang Taifen, Li Yuyan, Yi Wuyong, Shao Mumin, Li Shunmin, Yi Tiegang, Sun Huili
Department of Nephrology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine Shenzhen, Guangdong, China.
Department of Pathology, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine Shenzhen, Guangdong, China.
Am J Transl Res. 2019 Feb 15;11(2):855-864. eCollection 2019.
Chronic kidney disease (CKD) is commonly characterized by proteinuria and leads to progressive glomerulosclerosis and tubulointerstitial fibrosis. Accumulating evidence implicates mitochondrial dysfunction including reactive oxygen species (ROS) overproduction in the pathogenesis of CKD. Mitochondrial function and ROS production are regulated by mitochondrial uncoupling. Niclosamide ethanolamine salt (NEN) is a mild mitochondrial uncoupler, which reduces urinary albumin excretion in mice with diabetic kidney disease. However, its role in nondiabetic kidney disease has not been investigated. Here we show that NEN exerts renoprotective effects in adriamycin induced nondiabetic kidney disease. It reduces urinary protein excretion, restores podocyte function, ameliorates renal pathological injury, and decreases the excretion of the urinary tubular injury biomarkers NGAL and Kim-1. Specifically, NEN uncouples isolated kidney mitochondria, and dose-dependently decreases the renal production and urinary excretion of HO. Moreover, NEN increases catalase and PGC-1α expression, which might accelerate HO scavenging. The results of this study provide the first evidence that NEN protects kidney in nondiabetic kidney disease by regulating redox balance.
慢性肾脏病（CKD）通常以蛋白尿为特征，并导致进行性肾小球硬化和肾小管间质纤维化。越来越多的证据表明，线粒体功能障碍，包括活性氧（ROS）过度产生，参与了CKD的发病机制。线粒体功能和ROS产生受线粒体解偶联调节。尼可刹米乙醇胺盐（NEN）是一种温和的线粒体解偶联剂，可减少糖尿病肾病小鼠的尿白蛋白排泄。然而，其在非糖尿病肾病中的作用尚未得到研究。在此，我们表明NEN在阿霉素诱导的非糖尿病肾病中发挥肾脏保护作用。它可减少尿蛋白排泄，恢复足细胞功能，改善肾脏病理损伤，并减少肾小管损伤生物标志物中性粒细胞明胶酶相关脂质运载蛋白（NGAL）和肾损伤分子-1（Kim-1）的排泄。具体而言，NEN使分离的肾线粒体解偶联，并剂量依赖性地降低肾脏中HO的产生和尿排泄。此外，NEN增加过氧化氢酶和过氧化物酶体增殖物激活受体γ辅激活因子-1α（PGC-1α）的表达，这可能加速HO的清除。本研究结果首次证明NEN通过调节氧化还原平衡在非糖尿病肾病中保护肾脏。
