APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury

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.

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.…”

“…Unlike the GKT compounds, APX-115 is a pan-Nox inhibitor. Our study in type 2 diabetic kidney injury with db/db mice suggested that APX-115 was more effective than GKT compound in decreasing plasma isoprostanes (a lipid peroxidation and oxidative stress marker), serum creatinine, urinary albumin excretion, as well as mesangial expansion [17]. Nox 1 and 2 are the major sources of ROS in the artery wall in condition such as hypertension, hypercholesterolemia, as well as aging [25].…”

“…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.…”

“…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.…”

Role of the Nox4/AMPK/mTOR signaling axe in adipose inflammation-induced kidney injury

“…In db/db and db/m diabetic mice, treatment with APX-115, a novel pan-NOX-inhibitor, or GKT, enhanced lipid profile, attenuated insulin resistance, and reduced F4/80-positive cells, a marker of macrophage infiltration in fat tissue. Furthermore, there was a significant decrease in mRNA expression of inflammatory chemokines such as Plasminogen activator inhibitor-1 (PAI-1) and MCP-1 upon NOX inhibition [137].…”