APX-115, a pan-NADPH oxidase inhibitor, protects development of diabetic nephropathy in podocyte specific NOX5 transgenic mice
- 주제(키워드) Diabetic nephropathy , NADPH oxidase , Oxidative stress , Inflammation
- 주제(기타) Biochemistry & Molecular Biology
- 주제(기타) Endocrinology & Metabolism
- 설명문(일반) [Lee, Eun Soo; Kim, Hong Min; Lee, Sun Hee; Ha, Kyung Bong; Chung, Choon Hee] Yonsei Univ, Wonju Coll Med, Dept Internal Med, Wonju, South Korea; [Bae, Yoon Soo] Ewha Womans Univ, Dept Life Sci, Seoul, South Korea; [Lee, Soo Jin; Moon, Sung Hwan] Aptabio Therapeut Inc, Yongin, South Korea; [Lee, Eun Young] Soonchunhyang Univ, Cheonan Hosp, Dept Internal Med, Cheonan, South Korea; [Lee, Eun Young] Soonchunhyang Univ, Coll Med, Inst Tissue Regenerat, Cheonan, South Korea; [Lee, Ji-Hye] Soonchunhyang Univ, Cheonan Hosp, Dept Pathol, Cheonan, South Korea
- 등재 SCIE, SCOPUS
- 발행기관 ELSEVIER SCIENCE INC
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000175104
- 본문언어 영어
- Published As http://dx.doi.org/10.1016/j.freeradbiomed.2020.09.024
- PubMed https://pubmed.ncbi.nlm.nih.gov/33011273
초록/요약
NADPH oxidases (NOXs) are comprised of different isoforms, NOX1 to 5 and Duox1 and 2, and they trigger diabetic nephropathy (DN) in the patients with diabetes mellitus. Recently, it was shown that, compared to the other isoforms, the expression of NOX5 was increased in the patients with DN and, NOX5 has been suggested to be important in the development of therapeutic agents. The effect of pan-NOX inhibition by APX-115 has also been investigated in type 2 diabetic mice. However, since NOX5 is absent in mice, we evaluated the effect of pan-NOX inhibition by APX-115 in Nox5 transgenic mouse. Wild type and renal podocyte specific NOX5 transgenic mice (NOX5 pod+) were fed with high-fat diet (60% kcal fat) and treated with APX-115 (60 mg/kg) by oral gavage for 14 weeks. APX-115 significantly improved pancreatic beta cell function by decreased fasting blood glucose levels and increased insulin levels. Further, the total serum cholesterol, triglycerides, and urinary albumin/creatinine levels were also significantly decreased by APX-115 treatment. Increased NOX5 mRNA expressions, increased desmin levels, and reduced podocin protein expressions in the kidney of NOX5 pod + mice were also significantly restored to normal levels by APX-115 treatment. Moreover, APX-115 inhibited the expression of inflammation related proteins such as TRAF6. Collectively, these data suggest that APX-115 might be a promising therapeutic agent for the treatment of DN because of its pan-NOX inhibitory activity, including its NOX5 inhibitory activity, and also owing to its antiinflammatory effect.
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