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Temporary Angiotensin II Blockade at the Prediabetic Stage Attenuates the Development of Renal Injury in Type 2 Diabetic Rats

Yukiko Nagai^*, Li Yao, Hiroyuki Kobori^||, Kayoko Miyata, Yuri Ozawa^||, Akira Miyatake^*, Tokihito Yukimura^¶, Takatomi Shokoji, Shoji Kimura, Hideyasu Kiyomoto, Masakazu Kohno, Youichi Abe and Akira Nishiyama

^* The Research Equipment Center, Department of Pharmacology, RI Research Center, and Second Department of Internal Medicine, Kagawa Medical University, Kagawa, Japan; ^|| Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana; and ^¶ Department of Pharmacology, Osaka City University Graduate School of Medicine, Osaka, Japan

Address correspondence to: Dr. Akira Nishiyama, Department of Pharmacology, Kagawa Medical University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. Phone: +81-87-898-5111 ext. 2502; Fax: +81-87-891-2126; E-mail: akira{at}kms.ac.jp

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 AT₁ 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_proteinV) 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_proteinV, 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.

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