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01.09.2012 | Article

Deletion of p47 ^phox attenuates the progression of diabetic nephropathy and reduces the severity of diabetes in the Akita mouse

verfasst von: G. C. Liu, F. Fang, J. Zhou, K. Koulajian, S. Yang, L. Lam, H. N. Reich, R. John, A. M. Herzenberg, A. Giacca, G. Y. Oudit, J. W. Scholey

Erschienen in: Diabetologia | Ausgabe 9/2012

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Abstract

Aims/hypothesis

Reactive oxygen species (ROS) contribute to diabetes-induced glomerular injury and endoplasmic reticulum (ER) stress-induced beta cell dysfunction, but the source of ROS has not been fully elucidated. Our aim was to determine whether p47^phox-dependent activation of NADPH oxidase is responsible for hyperglycaemia-induced glomerular injury in the Akita mouse, a model of type 1 diabetes mellitus resulting from ER stress-induced beta cell dysfunction.

Methods

We examined the effect of deleting p47 ^phox (also known as Ncf1), the gene for the NADPH oxidase subunit, on diabetic nephropathy in the Akita mouse (Ins2 ^WT/C96Y) by studying four groups of mice: (1) non-diabetic mice (Ins2 ^WT/WT /p47 ^phox+/+); (2) non-diabetic p47 ^phox-null mice (Ins2 ^WT/WT /p47 ^phox−/−); (3) diabetic mice: (Ins2 ^WT/C96Y /p47 ^phox+/+); and (4) diabetic p47 ^phox-null mice (Ins2 ^WT/C96Y /p47 ^phox−/−). We measured the urinary albumin excretion rate, oxidative stress, mesangial matrix expansion, and plasma and pancreatic insulin concentrations in 16-week-old mice; we also measured glucose tolerance and insulin sensitivity, islet and glomerular NADPH oxidase activity and subunit expression, and pro-fibrotic gene expression in 8-week-old mice. In addition, we measured NADPH oxidase activity, subunit expression and pro-fibrotic gene expression in high glucose-treated murine mesangial cells.

Results

Deletion of p47 ^phox reduced kidney hypertrophy, oxidative stress and mesangial matrix expansion, and also reduced hyperglycaemia by increasing pancreatic and circulating insulin concentrations. p47 ^phox−/− mice exhibited improved glucose tolerance, but modestly decreased insulin sensitivity. Deletion of p47 ^phox attenuated high glucose-induced activation of NADPH oxidase and pro-fibrotic gene expression in glomeruli and mesangial cells.

Conclusions/interpretation

Deletion of p47 ^phox attenuates diabetes-induced glomerular injury and beta cell dysfunction in the Akita mouse.

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Titel: Deletion of p47 phox attenuates the progression of diabetic nephropathy and reduces the severity of diabetes in the Akita mouse
verfasst von: G. C. Liu
F. Fang
J. Zhou
K. Koulajian
S. Yang
L. Lam
H. N. Reich
R. John
A. M. Herzenberg
A. Giacca
G. Y. Oudit
J. W. Scholey
Publikationsdatum: 01.09.2012
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 9/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2586-1

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Abstract

Aims/hypothesis

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