Journal
ONCOTARGET
Volume 8, Issue 43, Pages 74217-74232Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.18540
Keywords
APX-115; diabetic kidney disease; mitochondria and peroxisome; oxidative stress; pan-Nox inhibitor
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Funding
- Korea Health Technology R&D project through Korea Health Industry Development Institute, Republic of Korea [HI14C0223]
- National Research Foundation, Republic of Korea [2016R1A2B4006575]
- Korean Research Fellowship program, Republic of Korea [2015H1D3A1062189]
- National Research Foundation of Korea [2016R1A2B4006575] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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