Temporary angiotensin II blockade at the prediabetic stage attenuates the development of renal injury in type 2 diabetic rats

• Published in: Journal of the American Society of Nephrology 2005-03, Vol.16 (3), p.703-711
• Main Authors: NAGAI, Yukiko, LI YAO, KOHNO, Masakazu, ABE, Youichi, NISHIYAMA, Akira, KOBORI, Hiroyuki, MIYATA, Kayoko, OZAWA, Yuri, MIYATAKE, Akira, YUKIMURA, Tokihito, SHOKOJI, Takatomi, KIMURA, Shoji, KIYOMOTO, Hideyasu
• Format: Article
• Language: English
• Subjects: Angiotensin II - genetics; Angiotensin II Type 1 Receptor Blockers - pharmacology; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Antihypertensive Agents - pharmacology; Biological and medical sciences; Blood Glucose; Blood Pressure; Body Weight; Collagen - metabolism; Connective Tissue Growth Factor; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - prevention & control; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - prevention & control; Drug Therapy, Combination; Hydralazine - pharmacology; Imidazoles - pharmacology; Immediate-Early Proteins - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Male; Medical sciences; NADPH Oxidases - metabolism; Nephrology. Urinary tract diseases; Olmesartan Medoxomil; Pharmacology. Drug treatments; Prediabetic State - drug therapy; Rats; Rats, Inbred OLETF; Receptors, Angiotensin - genetics; Renin - genetics; Tetrazoles - pharmacology; Thiazepines - pharmacology; Thiobarbituric Acid Reactive Substances - metabolism; Transforming Growth Factor beta - metabolism; Urinary system
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2004080649

Whether temporary angiotensin II (AngII) blockade at the prediabetic stage attenuates renal injury in type 2 diabetic OLETF rats later in life was investigated. OLETF rats were treated with an AT(1) receptor antagonist (olmesartan, 0.01% in food), angiotensin-converting enzyme inhibitor (temocapril, 0.01% in food), a combination of the two, or hydralazine (25 mg/kg per d) at the prediabetic stage (4 to 11 wk of age) and then monitored without further treatment until 50 wk of age. At 11 wk of age, blood glucose levels and urinary protein excretion (U(protein)V) were similar between OLETF and control LETO rats. However, OLETF rats showed higher kidney AngII contents and type IV collagen mRNA expression than LETO rats at this age. These decreased with olmesartan, temocapril, and a combination of these but not with hydralazine. At 50 wk of age, diabetic OLETF rats showed higher BP, U(protein)V, and intrarenal AngII levels than LETO rats. Temporary AngII blockade did not affect glucose metabolism or the development of hypertension in OLETF rats but significantly suppressed proteinuria and ameliorated glomerular injury. However, no parameters were affected by temporary hydralazine treatment. The present study demonstrated that intrarenal AngII and type IV collagen expression are already augmented long before diabetes becomes apparent in OLETF rats. Furthermore, temporary AngII blockade at the prediabetic stage attenuates the progression of renal injury in these animals. These data suggest that early AngII blockade could be an effective strategy for preventing the development of type 2 diabetic renal injury later in life.