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Deletion of p47phox attenuates the progression of diabetic nephropathy and reduces the severity of diabetes in the Akita mouse.

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.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Liu GC,Fang F,Zhou J,Koulajian K,Yang S,Lam L,Reich HN,John R,Herzenberg AM,Giacca A,Oudit GY,Scholey JW

doi

10.1007/s00125-012-2586-1

subject

Has Abstract

pub_date

2012-09-01 00:00:00

pages

2522-32

issue

eissn

0012-186X

issn

1432-0428

journal_volume

pub_type

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Deletion of p47phox attenuates the progression of diabetic nephropathy and reduces the severity of diabetes in the Akita mouse.