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.