Benazepril, an angiotensin-converting enzyme inhibitor, alleviates renal injury in spontaneously hypertensive rats by inhibiting advanced glycation end-product-mediated pathways.
1. Advanced glycation end-products (AGE) and their receptors (RAGE) have been implicated in renal damage in diabetes. The aim of the present study was to investigate the effects of benazepril, an angiotensin-converting enzyme inhibitor (ACEI), on the formation of AGE, the expression RAGE and other associated components in the oxidative stress pathway in spontaneously hypertensive rats (SHR). 2. Groups of SHR were treated with or without 10 mg/kg per day benazepril for 12 weeks. Systolic blood pressure (SBP) and angiotensin (Ang) II levels were evaluated in SHR and control Wistar-Kyoto (WKY) rats. Renal function was investigated by determining levels of proteinuria and glomerulosclerosis. Furthermore, reactive oxygen species (ROS) in the rat renal cortex were analysed using an H(2)O(2)-based hydroxyl radical-detection assay and the renal content of AGE, RAGE, NADPH oxidase p47phox, nuclear factor (NF)-kappaB p65, phosphorylated (p-) NF-kappaB p65, vascular cell adhesion molecule (VCAM)-1 and transforming growth factor (TGF)-beta1 was determined by immunohistochemistry, quantitative real-time polymerase chain reaction and western blot analysis. 3. Treatment with benazepril inhibited the formation of AngII, reduced SBP and alleviated renal lesions in SHR compared with both untreated SHR and control WKY rats. Benazepril treatment significantly suppressed the accumulation of AGE and expression of RAGE in the kidney of SHR. In addition, benazepril treatment reduced the upregulation of NADPH oxidase p47phox, ROS generation and NF-kappaB p65, p-NF-kappaB p65, VCAM-1 and TGF-beta1 expression in the kidney of SHR compared with both untreated SHR and control WKY rats. 4. The results of the present study provide new insights into the regulation by the renin-angiotensin system of AGE-RAGE, oxidative stress and nephropathy, increasing our understanding of the role of the RAS in nephropathy.
Liu
Xue-Ping
XP
Department of Geriatrics, Shandong Provincial Hospital of Shandong University, Jinan, China. lxp6133@yahoo.com.cn
Pang
Yue-Jiu
YJ
Zhu
Wei-Wei
WW
Zhao
Ting-Ting
TT
Zheng
Min
M
Wang
Yi-Bing
YB
Sun
Zhi-Jian
ZJ
Sun
Siao-Jing
SJ
D000804:Angiotensin II / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007672:Kidney Cortex / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011507:Proteinuria / Q000378:metabolism / Q000517:prevention & control; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001552:Benzazepines; D017127:Glycation End Products, Advanced; D010982:Platelet-Derived Growth Factor; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; C044946:benazepril