NADPH oxidase NOX1 is involved in activation of protein kinase C and premature senescence in early stage diabetic kidney

Autor: Misaki Matsumoto, Kazumi Iwata, Jia Zhang, Masakazu Ibi, Chihiro Yabe-Nishimura, Kai Zhu, Masato Katsuyama, Ashraf Taye, Kumar Sharma, Junjie Liu, Yoichi Ohshima, Xiaopeng Wen, Tomoko Kakehi, ChunYuan Fan
Rok vydání: 2014
Předmět:
Male
medicine.medical_specialty
Renal cortex
Blotting
Western
Biology
Real-Time Polymerase Chain Reaction
Biochemistry
p38 Mitogen-Activated Protein Kinases
Diabetes Mellitus
Experimental
Diabetic nephropathy
Immunoenzyme Techniques
chemistry.chemical_compound
Mice
Physiology (medical)
Internal medicine
medicine
Animals
Diabetic Nephropathies
NADH
NADPH Oxidoreductases
RNA
Messenger
Protein kinase A
Protein kinase C
Cells
Cultured
Cellular Senescence
Protein Kinase C
Mice
Knockout
NADPH oxidase
Reverse Transcriptase Polymerase Chain Reaction
Streptozotocin
medicine.disease
beta-Galactosidase
Glomerular Mesangium
Mice
Inbred C57BL
Oxidative Stress
Endocrinology
medicine.anatomical_structure
chemistry
NOX1
Hyperglycemia
biology.protein
NADPH Oxidase 1
Reactive Oxygen Species
Oxidation-Reduction
Nicotinamide adenine dinucleotide phosphate
medicine.drug
Signal Transduction
Zdroj: Free radical biologymedicine. 83
ISSN: 1873-4596
Popis: 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.
Databáze: OpenAIRE
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