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

Author:
Zhu, Kai   Kakehi, Tomoko   Matsumoto, Misaki   Iwata, Kazumi   Ibi, Masakazu   Ohshima, Yoichi   Zhang, Jia   Liu, Junjie   Wen, Xiaopeng   Taye, Ashraf   Fan, Chunyuan   Katsuyama, Masato   Sharma, Kumar   Yabe-Nishimura, Chihiro  


Journal:
Free Radical Biology and Medicine


Issue Date:
2015


Abstract(summary):

Highlights

Nox1 mRNA was upregulated in the renal cortex of mice at 3 weeks of hyperglycemia.

NOX1 is involved in increased oxidative stress in diabetic kidney.

NOX1 elicits activation of PKC and phosphorylation of p38 MAPK.

NOX1 promotes hyperglycemia-induced renal senescence via the p38/p27Kip1 pathway.

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, p16INK4A and p21Cip1, were equivalent between the genotypes, increased levels of p27Kip1 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/p27Kip1 signaling pathway by activating PKC and promotes premature senescence in early stage diabetic nephropathy.



Page:
21-30


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