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Abstract
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.
Highlights
Diabetic kidney disease (DKD) is a key microvascular complication of diabetes and the most common cause of end-stage kidney disease (ESKD) [1]
With respect to lipid metabolism, we evaluated the effect of both APX-115 and losartan on peroxisomal as well as mitochondrial biogenesis
The present data demonstrated that orally administrated APX-115, a pan-Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) inhibitor, could exert a renoprotective effect in STZ-induced diabetic mice as much as losartan
Summary
Diabetic kidney disease (DKD) is a key microvascular complication of diabetes and the most common cause of end-stage kidney disease (ESKD) [1]. Since clinical trials of several antioxidants against oxidative stress-associated tissue injury have failed [6], inhibiting reactive oxygen species (ROS) generation might become a promising strategy to treat DKD. In the experimental models of chronic kidney disease (CKD) including DKD, Nox expression and activity are increased in the kidney [11,12,13,14,15,16,17]. In a streptozotocin (STZ)-induced type 1 diabetes rodent model, increased expression of Nox is associated with ROS-induced kidney damage [15,16,17], while Nox www.impactjournals.com/oncotarget knockout can protect STZ-induced diabetic mice against glomerular injury [18]. Nox1/4 dual inhibitor GKT137831 can block high glucose-induced activation of Nox4-associated oxidative stress and pro-fibrotic signaling in mouse proximal tubular epithelial cells [13]. GKT137831 and GKT136901 can effectively reduce oxidative stress, albuminuria, and kidney fibrosis in mouse models of type 1 and type 2 diabetes [19, 20]
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