title: ADAM17 mediates Nox4 expression and NADPH oxidase activity in the kidney cortex of OVE26 mice.
abstract: Matrix protein accumulation is a prominent feature of diabetic nephropathy that contributes to renal fibrosis and decline in renal function. The pathogenic mechanisms of matrix accumulation are incompletely characterized. We investigated if the matrix metalloprotease a disintegrin and metalloprotease1 7 (ADAM17), known to cleave growth factors and cytokines, is activated in the kidney cortex of OVE26 type 1 diabetic mice and the potential mechanisms by which ADAM17 mediates extracellular matrix accumulation. Protein expression and activity of ADAM17 were increased in OVE26 kidney cortex. Using a pharmacological inhibitor to ADAM17, TMI-005, we determined that ADAM17 activation results in increased type IV collagen, Nox4, and NADPH oxidase activity in the kidney cortex of diabetic mice. In cultured mouse proximal tubular epithelial cells (MCTs), high glucose increases ADAM17 activity, Nox4 and fibronectin expression, cellular collagen content, and NADPH oxidase activity. These effects of glucose were inhibited when cells were pretreated with TMI-005 and/or transfected with small interfering ADAM17. Collectively, these data indicate a novel mechanism whereby hyperglycemia in diabetes increases extracellular matrix protein expression in the kidney cortex through activation of ADAM17 and enhanced oxidative stress through Nox enzyme activation. Additionally, our study is the first to provide evidence that Nox4 is downstream of ADAM17.
authors.affiliation: Department of Medicine, Division of Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Bridget M
authors.initials: BM
authors.lastname: Ford
authors.forename: Assaad A
authors.initials: AA
authors.lastname: Eid
authors.forename: Monika
authors.initials: M
authors.lastname: Göőz
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Barnes
authors.forename: Yves C
authors.initials: YC
authors.lastname: Gorin
authors.forename: Hanna E
authors.initials: HE
authors.lastname: Abboud
mesh_terms: D051722:ADAM Proteins / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D024141:Collagen Type IV / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D007672:Kidney Cortex / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D051379:Mice; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology
chemical_list: D024141:Collagen Type IV; D005353:Fibronectins; D034741:RNA, Small Interfering; D003094:Collagen; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; D005947:Glucose
keywords: ADAM17; Nox4; OVE26 mice; diabetic nephropathy; extracellular matrix