Advanced Oxidation Protein Products Promote Inflammation in Diabetic Kidney through Activation of Renal Nicotinamide Adenine Dinucleotide Phosphate Oxidase

• Published in: Endocrinology (Philadelphia) 2008-04, Vol.149 (4), p.1829-1839
• Main Authors: Shi, Xiao Yun, Hou, Fan Fan, Niu, Hong Xin, Wang, Guo Bao, Xie, Di, Guo, Zhi Jian, Zhou, Zhan Mei, Yang, Fang, Tian, Jian Wei, Zhang, Xun
• Format: Article
• Language: English
• Subjects: Abnormalities; Accumulation; Adenine; Animals; Biological and medical sciences; Chemokine CCL2 - genetics; Diabetes; Diabetes mellitus; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - etiology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme Activation; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fibronectin; Fundamental and applied biological sciences. Psychology; Hypertrophy; Inflammation; Kidney - metabolism; Kidney - pathology; Kidneys; Macrophages; Male; Medical sciences; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; NAD(P)H oxidase; NADPH Oxidases - physiology; NADPH-diaphorase; Nephritis - etiology; Nephropathy; Nicotinamide; Nicotinamide adenine dinucleotide; Oral administration; Oxidase; Oxidation; Oxidation-Reduction; Pathogenesis; Proteins; Proteins - metabolism; Rats; Rats, Sprague-Dawley; Serum albumin; Streptozocin; Structure-function relationships; Transforming Growth Factor beta1 - genetics; Transforming growth factor-b1; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-1544

The involvement of inflammatory processes has been recognized in development and/or progression of diabetic nephropathy. However, the mechanisms involved in the pathogenesis of renal inflammation have not been completely understood. In this study, we tested the hypothesis that accumulation of advanced oxidation protein products (AOPPs), which occurs in diabetes, may promote inflammatory responses in diabetic kidney. Streptozotocin-induced diabetic rats were randomized to iv injection of vehicle, native rat serum albumin (RSA), and AOPPs-modified RSA (AOPPs-RSA) in the presence or absence of oral administration of apocynin. A control group was followed concurrently. Compared with RSA- or vehicle-treated diabetic rats, AOPPs-RSA-treated animals displayed significant increase in renal macrophage infiltration and overexpression of monocyte chemoattractant protein-1 and TGF-β1. This was associated with deteriorated structural and functional abnormalities of diabetic kidney, such as glomerular hypertrophy, fibronectin accumulation, and albuminuria. AOPP challenge significantly increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-dependent superoxide generation in renal homogenates and up-regulated membrane expression of renal NADPH oxidase subunits p47phox and gp91phox. All these AOPPs-induced perturbations in diabetic kidney could be prevented by the NADPH oxidase inhibitor apocynin. These data suggest that chronic accumulation of AOPPs may promote renal inflammation in diabetes probably through activation of renal NADPH oxidase.