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

Autor: Gayoung Lee, Kitae Kim, Jee Young Han, Young Sun Kang, Sung Chan Lee, Jung Eun Kim, Hyunwook Kim, Dae Ryong Cha, Yun Soo Bae, Sung Hwan Moon, Hunjoo Ha, Hye Sook Min, Sae Rom Lee, Ganghyun Kim, Ji Eun Lee, Jin Joo Cha, Jung Yeon Ghee
Rok vydání: 2016
Předmět:
0301 basic medicine
Male
Time Factors
Pyridines
Adipose tissue
Gene Expression
030204 cardiovascular system & hematology
medicine.disease_cause
Kidney
Diabetic nephropathy
0302 clinical medicine
Transforming Growth Factor beta
Diabetic Nephropathies
Enzyme Inhibitors
Pyrazolones
Cells
Cultured
Mice
Knockout
NADPH oxidase
biology
Reverse Transcriptase Polymerase Chain Reaction
food and beverages
NOX4
Organ Size
Lipids
Isoenzymes
medicine.anatomical_structure
Mesangial Cells
cardiovascular system
Cytokines
Female
medicine.medical_specialty
Pyridones
Blotting
Western
Protective Agents
Pathology and Forensic Medicine
03 medical and health sciences
Internal medicine
Diabetes mellitus
medicine
Animals
Molecular Biology
business.industry
Kidney metabolism
NADPH Oxidases
Cell Biology
medicine.disease
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
Diabetes Mellitus
Type 2
biology.protein
Pyrazoles
Lipid Peroxidation
business
Reactive Oxygen Species
Oxidative stress
Zdroj: Laboratory investigation; a journal of technical methods and pathology. 97(4)
ISSN: 1530-0307
Popis: 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.
Databáze: OpenAIRE
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