Kwon Guideock, Uddin Md Jamal, Lee Gayoung, Jiang Songling, Cho Ahreum, Lee Jung Hwa, Lee Sae Rom, Bae Yun Soo, Moon Sung Hwan, Lee Soo Jin, Cha Dae Ryong, Ha Hunjoo
Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.
Department of Life Science, Ewha Womans University, Seoul, Korea.
Oncotarget. 2017 Jun 16;8(43):74217-74232. doi: 10.18632/oncotarget.18540. eCollection 2017 Sep 26.
NADPH oxidase (Nox)-derived reactive oxygen species (ROS) are increasingly recognized as a key factor in inflammation and extracellular matrix accumulation in diabetic kidney disease. APX-115 (3-phenyl-1-(pyridin-2-yl)-4-propyl-1-5-hydroxypyrazol HCl) is a novel orally active pan-Nox inhibitor. The objective of this study was to compare the protective effect of APX-115 with a renin-angiotensin system inhibitor (losartan), the standard treatment against kidney injury in diabetic patients, on streptozotocin (STZ)-induced diabetic kidney injury. Diabetes was induced by intraperitoneal injection of STZ at 50 mg/kg/day for 5 days in C57BL/6J mice. APX-115 (60 mg/kg/day) or losartan (1.5 mg/kg/day) was administered orally to diabetic mice for 12 weeks. APX-115 effectively prevented kidney injury such as albuminuria, glomerular hypertrophy, tubular injury, podocyte injury, fibrosis, and inflammation as well as oxidative stress in diabetic mice, similar to losartan. In addition, both APX-115 and losartan treatment effectively inhibited mitochondrial and peroxisomal dysfunction associated with lipid accumulation. Our data suggest that APX-115, a pan-Nox inhibitor, may become a novel therapeutic agent against diabetic kidney disease by maintaining peroxisomal and mitochondrial fitness.
烟酰胺腺嘌呤二核苷酸磷酸氧化酶（Nox）衍生的活性氧（ROS）越来越被认为是糖尿病肾病炎症和细胞外基质积累的关键因素。APX-115（3-苯基-1-（吡啶-2-基）-4-丙基-1,5-羟基吡唑盐酸盐）是一种新型口服活性泛Nox抑制剂。本研究的目的是比较APX-115与肾素-血管紧张素系统抑制剂（氯沙坦）（糖尿病患者肾脏损伤的标准治疗药物）对链脲佐菌素（STZ）诱导的糖尿病肾脏损伤的保护作用。通过以50mg/kg/天的剂量腹腔注射STZ，连续5天，诱导C57BL/6J小鼠患糖尿病。将APX-115（60mg/kg/天）或氯沙坦（1.5mg/kg/天）口服给予糖尿病小鼠，持续12周。与氯沙坦类似，APX-115有效预防了糖尿病小鼠的肾脏损伤，如蛋白尿、肾小球肥大、肾小管损伤、足细胞损伤、纤维化和炎症以及氧化应激。此外，APX-115和氯沙坦治疗均有效抑制了与脂质积累相关的线粒体和过氧化物酶体功能障碍。我们的数据表明，泛Nox抑制剂APX-115可能通过维持过氧化物酶体和线粒体健康状态，成为治疗糖尿病肾病的新型治疗药物。
