A novel pan-Nox inhibitor, APX-115, protects kidney injury in streptozotocin-induced diabetic mice: possible role of peroxisomal and mitochondrial biogenesis

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.

A pan-NADPH Oxidase Inhibitor Ameliorates Kidney Injury in Type 1 Diabetic Rats

“…Our previous studies completed in both type 1 and 2 diabetic mice demonstrated that APX-115 has a comparative renoprotective effect to losartan (a mainstay treatment in DKD) and GKT137831 (a dual Nox inhibitor) respectively [17,18]. Particularly, the present study provides additional confirmatory evidence in another murine model and shows the dose-dependent effect of APX-115 in diabetic kidney injury.…”

“…Nox family is one of the major contributors on ROS generation in the kidney [10]. Our previous studies with db/db and STZ-induced mice have implied increases of protein and mRNA levels of renal Nox 1, 2, and 4, which were significantly reduced by APX-115, a panNox inhibitor [17,18]. We consistently showed that excessive oxidative stress was significantly attenuated by APX-115, particularly at dose of 5 and 30 mg/kg, as well as losartan.…”

“…The diabetic rats were orally administered with either 0.5, 5, or 30 mg/kg/day of APX-115 (3-phenyl-1-(pyridine-2-yl)-4-propyl-1-5-hydroxypyazol HCl) (AptaBio Therapeutics Inc, Yongin, South Korea) or 1 mg/kg/day of losartan for 8 weeks. The dose of losartan was selected based on our previous pharmacological study in diabetic mice [18] and pharmacokinetic difference between rats and mice [20]. The chemical synthesis and characteristics of APX-115 are as previously described [21].…”

“…APX-115 is a novel orally active pan-Nox inhibitor, which has been shown to protect against DKD in type 2 diabetic db/db mice [17] as well as in streptozotocin (STZ)-induced type 1 diabetic mice [18]. As these standard diabetic mice model cannot fully mimic human DKD progression [19], the present study utilized rats as a murine model for type 1 diabetes.…”

PGC‐1α, a potential therapeutic target against kidney aging

“…Kidney specimens from CKD patients show decreased PGC‐1α expression (Han et al, ; Sharma et al, ), which is associated with a decreased GFR in human kidney fibrosis (Lemos et al, ). PGC‐1α is decreased in various models of CKD, including unilateral ureteral obstruction‐induced fibrosis (Han et al, ), db/db diabetic mice (Hong et al, ; Kim, Lee, et al, ; Kim, Lim, et al ; Long et al, ; Yuan et al, ; Zhang, Liu, Zhou, Wang, & Chen, ), and streptozotocin‐induced diabetic mice (Kwon et al, ). Our results also show that PGC‐1α expression is significantly decreased in diabetic mice (Figure ).…”