Debra Dorotea1, Guideock Kwon1, Jung Hwa Lee1, Erika Saunders2, Yun Soo Bae3, Sung Hwan Moon4, Soo Jin Lee4, Dae Ryong Cha5, Hunjoo Ha1. 1. Graduate School of Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Republic of Korea. 2. School of Pharmacy, University of Maryland, Baltimore, Maryland, USA. 3. Department of Life Science, Ewha Womans University, Seoul, Republic of Korea. 4. Aptabio Therapeutics Inc., Yongin, Republic of Korea. 5. Department of Nephrology, Korea University Ansan Hospital, Ansan, Republic of Korea.
Abstract
BACKGROUND: NADPH oxidases (Nox) is a major enzyme system contributing to oxidative stress, which plays an important role in the pathogenesis of diabetic kidney disease (DKD). We have shown an elevation of renal Nox1, Nox2, and Nox4 in diabetic mice. APX-115, a pan-Nox inhibitor, attenuated the progression of DKD in mice. As the standard diabetic mice cannot fully mimic human DKD, the present study was aimed to show the dose-dependent effect and to provide a confirmatory evidence of APX-115 in attenuating DKD in diabetic rats. METHOD: Type 1 diabetes was induced by a single 60 mg/kg intraperitoneal injection of streptozotocin in Sprague-Dawley rats. 0.5, 5, or 30 mg APX-115/kg/day or losartan 1 mg/kg/day were administered orally to diabetic rats for 8 weeks. RESULTS: APX-115 treatment showed an improvement in kidney function and tubular and podocyte -injury, as well as attenuation of inflammation, fibrosis, and oxidative stress as much as losartan, a comparative drug and mainstay treatment in DKD. Therapeutic effect of APX-115 was exhibited in a dose-dependent manner; a dose of 30 mg/kg displayed a superior efficacy. CONCLUSION: This finding verified the pre-clinical data of APX-115 in protecting against DKD, which is important to bring APX-115 toward the next stage of drug development.
BACKGROUND: NADPH oxidases (Nox) is a major enzyme system contributing to oxidative stress, which plays an important role in the pathogenesis of diabetic kidney disease (DKD). We have shown an elevation of renal Nox1, Nox2, and Nox4 in diabeticmice. APX-115, a pan-Nox inhibitor, attenuated the progression of DKD in mice. As the standard diabeticmice cannot fully mimic human DKD, the present study was aimed to show the dose-dependent effect and to provide a confirmatory evidence of APX-115 in attenuating DKD in diabeticrats. METHOD: Type 1 diabetes was induced by a single 60 mg/kg intraperitoneal injection of streptozotocin in Sprague-Dawley rats. 0.5, 5, or 30 mg APX-115/kg/day or losartan 1 mg/kg/day were administered orally to diabeticrats for 8 weeks. RESULTS:APX-115 treatment showed an improvement in kidney function and tubular and podocyte -injury, as well as attenuation of inflammation, fibrosis, and oxidative stress as much as losartan, a comparative drug and mainstay treatment in DKD. Therapeutic effect of APX-115 was exhibited in a dose-dependent manner; a dose of 30 mg/kg displayed a superior efficacy. CONCLUSION: This finding verified the pre-clinical data of APX-115 in protecting against DKD, which is important to bring APX-115 toward the next stage of drug development.