APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury
Jin Joo Cha1, Hye Sook Min1, Ki Tae Kim1
1Department of Internal Medicine, Division of Nephrology, Korea University Ansan Hospital, Ansan, Korea.
Abstract:
Recent studies have suggested that renal Nox is important in the progression of diabetic nephropathy. Therefore, we investigated the effect of a novel pan-NOX-inhibitor, APX-115, on diabetic nephropathy in type 2 diabetic mice. Eight- week-old db/m and db/db mice were treated with APX-115 for 12 weeks. APX-115 was administered by oral gavage at a dose of 60 mg/kg per day. To compare the effects of APX-115 with a dual Nox1/Nox4 inhibitor, db/db mice were treated with GKT137831 according to the same protocol. APX-115 significantly improved insulin resistance in diabetic mice, similar to GKT137831. Oxidative stress as measured by plasma 8-isoprostane level was decreased in the APX-115 group compared with diabetic controls. All lipid profiles, both in plasma and tissues improved with Nox inhibition. APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. APX-115 decreased urinary albumin excretion and preserved creatinine level. In diabetic kidneys, APX-115 significantly improved mesangial expansion, but GKT137831 did not. In addition, F4/80 infiltration in the adipose tissue and kidney decreased with APX-115 treatment. We also found that TGF-β stimulated ROS generation in primary mouse mesangial cells (pMMCs) from wild-type, Nox1 KO, and Duox1 KO mice, but did not induce Nox activity in pMMCs from Nox2 knockout (KO), Nox4 KO, or Duox2 KO mice. These results indicate that activating Nox2, Nox4, or Duox2 in pMMCs is essential for TGF-β-mediated ROS generation. Our findings suggest that APX-115 may be as effective or may provide better protection than the dual Nox1/Nox4 inhibitor, and pan-Nox inhibition with APX-115 might be a promising therapy for diabetic nephropathy.
Insights
A novel pan-NOX inhibitor, APX-115, effectively treated diabetic nephropathy in mice by reducing oxidative stress and improving kidney function. This suggests APX-115 is a promising therapeutic for diabetic kidney disease.
Area of Science:
- Nephrology
- Endocrinology
- Biochemistry
Background:
- Diabetic nephropathy (DN) is a major complication of diabetes, linked to oxidative stress and renal NADPH oxidase (Nox) enzymes.
- Targeting Nox enzymes is a potential therapeutic strategy for DN.
Purpose of the Study:
- To investigate the efficacy of APX-115, a novel pan-Nox inhibitor, in a mouse model of type 2 diabetic nephropathy.
- To compare APX-115 with a dual Nox1/Nox4 inhibitor, GKT137831.
Main Methods:
- Type 2 diabetic (db/db) and control (db/m) mice were treated with APX-115 (60 mg/kg/day) or GKT137831 for 12 weeks.
- Evaluated insulin resistance, oxidative stress (8-isoprostane), lipid profiles, Nox protein expression, kidney function (albuminuria, creatinine), renal histology, and inflammatory markers (F4/80).
- Investigated TGF-β-induced ROS generation in primary mouse mesangial cells (pMMCs) with specific Nox knockout models.
Main Results:
- APX-115 improved insulin resistance, reduced oxidative stress, and normalized lipid profiles in diabetic mice.
- APX-115 decreased renal Nox1, Nox2, and Nox4 expression, reduced albuminuria, and preserved creatinine levels.
- APX-115 significantly improved mesangial expansion and reduced F4/80 infiltration in kidneys and adipose tissue, outperforming GKT137831 in histological improvement.
- TGF-β-induced ROS generation in pMMCs required Nox2, Nox4, or Duox2 activation.
Conclusions:
- Pan-Nox inhibition with APX-115 demonstrates significant renoprotective effects in diabetic nephropathy.
- APX-115 shows potential for superior efficacy compared to dual Nox1/Nox4 inhibition, suggesting it as a promising therapeutic strategy for DN.
