title: NADPH oxidase NOX1 is involved in activation of protein kinase C and premature senescence in early stage diabetic kidney.
abstract: Increased oxidative stress and activation of protein kinase C (PKC) under hyperglycemia have been implicated in the development of diabetic nephropathy. Because reactive oxygen species derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, NOX1 accelerate the translocation of PKC isoforms, NOX1 is postulated to play a causative role in the development of diabetic nephropathy. Hyperglycemia was induced in wild-type and Nox1-deficient mice (KO) by two doses of streptozotocin injection. At 3 weeks after the induction of hyperglycemia, glomeruli and cortical tubules were isolated from kidneys. The mRNA level of Nox1 was significantly upregulated in the renal cortex at 3 weeks of hyperglycemia. Urinary albumin and expression of inflammatory or fibrotic mediators were similarly elevated in diabetic wild-type and KO; however, increases in glomerular volume and mesangial matrix area were attenuated in diabetic KO. Nox1 deficiency significantly reduced the levels of renal thiobarbituric acid-reacting substances and 8-hydroxydeoxyguanosine, membranous translocation of PKCα/β, activity of PKC, and phosphorylation of p38 mitogen-activated protein kinase in the diabetic kidney. Furthermore, increased staining of senescence-associated β-galactosidase in glomeruli and cortical tubules of diabetic mice was significantly suppressed in KO. Whereas the levels of cyclin-dependent kinase inhibitors, p16(INK4A) and p21(Cip1), were equivalent between the genotypes, increased levels of p27(Kip1) and γ-H2AX, a biomarker for DNA double-strand breaks, were significantly attenuated in isolated glomeruli and cortical tubules of diabetic KO. Taken together, NOX1 modulates the p38/p27(Kip1) signaling pathway by activating PKC and promotes premature senescence in early stage diabetic nephropathy.
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kakehi
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Matsumoto
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Iwata
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ibi
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ohshima
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Junjie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Wen
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Taye
authors.affiliation: Dujiangyan City Medical Center, Dujiangyan Chengdu, 611830 Sichuan, China.
authors.forename: Chunyuan
authors.initials: C
authors.lastname: Fan
authors.affiliation: Radioisotope Center, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Katsuyama
authors.affiliation: Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, University of California at San Diego and VA San Diego Healthcare System, La Jolla, CA 92093, USA.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan. Electronic address: nchihiro@koto.kpu-m.ac.jp.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yabe-Nishimura
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D005920:Glomerular Mesangium / Q000378:metabolism / Q000473:pathology*; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009247:NADH, NADPH Oxidoreductases / Q000502:physiology*; D000074624:NADPH Oxidase 1; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D001616:beta-Galactosidase / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; C000614711:NOX1 protein, mouse; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D001616:beta-Galactosidase
keywords: Diabetic nephropathy; Free radicals; NADPH oxidase; NOX1; Protein kinase C; Senescence