Angiotensin II type I receptor blockade suppresses glomerular renin-angiotensin system activation, oxidative stress, and progressive glomerular injury in rat anti-glomerular basement membrane glomerulonephritis

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 158; no. 4; pp. 235 - 248
• Main Authors: Kinoshita, Yukiko, Kondo, Shuji, Urushihara, Maki, Suga, Kenichi, Matsuura, Sato, Takamatsu, Masanori, Shimizu, Maki, Nishiyama, Akira, Kawachi, Hiroshi, Kagami, Shoji
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.10.2011; Elsevier
• Subjects: Actins - metabolism; Angiotensin II - biosynthesis; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensinogen - biosynthesis; Animals; Anti-Glomerular Basement Membrane Disease - drug therapy; Anti-Glomerular Basement Membrane Disease - metabolism; Anti-Glomerular Basement Membrane Disease - pathology; Biological and medical sciences; General aspects; Glomerular Basement Membrane - pathology; Glomerulonephritis; Internal Medicine; Investigative techniques, diagnostic techniques (general aspects); Kidney Glomerulus - drug effects; Kidney Glomerulus - metabolism; Kidney Glomerulus - pathology; Male; Medical sciences; Membrane Glycoproteins - metabolism; NADPH Oxidase 2; NADPH Oxidases - metabolism; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Oxidative Stress - drug effects; Rats; Rats, Inbred WKY; Renin-Angiotensin System - drug effects; Superoxides - metabolism; Transforming Growth Factor beta1 - biosynthesis; Translational Medical Research; DHE; α-smooth muscle actin; IgA; MCP-1; WKY; RAS; transforming growth factor beta; angiotensinogen; systolic blood pressure; α-SMA; epithelial mesenchymal transition; FITC; GBM; reactive oxygen species; TGF-β; fluorescein isothiocyanate; IF; O 2; SBP; angiotensin II type I receptor; GN; immunoglobulin A; AT1R; EMT; AGT; Ang II; ECM; immunofluorescent; ARB; angiotensin II type I receptor blocker; dihydroethidium; angiotensin II; Nox; enzyme-linked immunosorbent assay; ROS; monocytes chemoattractant protein-1; Wistar Kyoto; glomerular basement membrane; nicotinamide adenine dinucleotide phosphate-oxidase; glomerulonephritis; superoxide; extracellular matrix; renin-angiotensin system; ELISA; Glomerulonephritis; Kidney disease; Oxidative stress; Urinary system disease; Rat; Rodentia; Activation; Trauma; Antibasement membrane glomerulonephritis; Medicine; Progressive; Vertebrata; Renin angiotensin system; Mammalia; Animal; Clinical biology; Angiotensin antagonist; Lesion
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2011.05.003

Excessive renin-angiotensin system (RAS) activation within the kidney induces not only renal oxidative stress but also renal scarring and dysfunction. This study examined the effects of an angiotensin II (Ang II) type I receptor (AT1R) blocker (ARB) on the progression of renal injury in rat anti-glomerular basement membrane glomerulonephritis (GN), with a particular focus on the participation of glomerular RAS activation in glomerular structural alterations, inflammation, and oxidative stress. Nephritic rats were divided into 2 groups and treated with vehicle or ARB until day 28. Treatment with ARB improved proteinuria significantly in nephritic rats. Vehicle-treated nephritic rats developed crescentic GN accompanied by marked macrophage infiltration and the enhanced expression of glomerular α-smooth muscle actin (α-SMA), angiotensinogen (AGT), Ang II, AT1R, and NADPH oxidase (Nox2) on days 7 and 28 of GN. ARB improved pathologic alterations such as crescent formation and glomerulosclerosis, and it had a significant inhibitory effect on the levels of these parameters on day 28 of GN. Enhanced superoxide production in nephritic glomeruli was decreased also by ARB. Moreover, Ang II and transforming growth factor beta (TGF-β) in the supernatant of cultured glomeruli was increased significantly in vehicle-treated nephritic rats whereas ARB inhibited the production of these compounds significantly on day 28. These results indicate that increased glomerular RAS activity and the resulting Ang II play important roles in progressive glomerular injury–the induction of oxidative stress and TGF-β expression, and they suggest that AT1R blockade attenuates proteinuria and progressive glomerular remodeling via the suppression of glomerular RAS activation in GN.