APX-115, a pan-NADPH oxidase inhibitor, protects development of diabetic nephropathy in podocyte specific NOX5 transgenic mice

Eun Soo Lee, Hong Min Kim, Sun Hee Lee, Kyung Bong Ha, Yoon Soo Bae, Soo Jin Lee, Sung Hwan Moon, Eun Young Lee, Ji Hye Lee, Choon Hee Chung

Research output: Contribution to journalArticlepeer-review

Abstract

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 anti-inflammatory effect.

Original languageEnglish
Pages (from-to)92-101
Number of pages10
JournalFree Radical Biology and Medicine
Volume161
DOIs
Publication statusPublished - 2020 Dec

Bibliographical note

Funding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea ( NRF) funded by the Ministry of Education ( 2016R1A6A3A11933581 ) and Korea government (Ministry of Science and ICT ) ( 2018R1A2B6005360 , 2020R1A2C2003438 ). And the authors would like to thank Dr. Chris R. Kennedy (Ottawa Hospital Research Institute, Ottawa, Canada) for kindly supplying NOX5 pod + mice.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Physiology (medical)

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