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

ABSTRACT: 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.

SUBMITTER: Nagai Y

PROVIDER: S-EPMC2572705 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

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

Nagai Yukiko Y Yao Li L Kobori Hiroyuki H Miyata Kayoko K Ozawa Yuri Y Miyatake Akira A Yukimura Tokihito T Shokoji Takatomi T Kimura Shoji S Kiyomoto Hideyasu H Kohno Masakazu M Abe Youichi Y Nishiyama Akira A

Journal of the American Society of Nephrology : JASN 20050112 3

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 ...[more]

PMID: 15647337

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Project description:Both angiotensin II type 1 receptor (AT1R) and nuclear factor-kappa B (NF-?B) play significant roles in the pathogenesis of hypertension and type 2 diabetes. However, the role of NF-?B in perpetuating renal AT1 receptors dysfunction remains unclear. The aim of the present study to determine whether blockade of NF-?B, could reverse the exaggerated renal AT1R function, reduce inflammatory state and oxidative stress, lower blood pressure in Zucker diabetic fatty (ZDF) rats.Pyrrolidine dithiocarbamate (PDTC), a NF-?B inhibitor (150 mg/kg in drinking water)or vehicle was administered orally to 12-weeks-old ZDF rats and their respective control lean Zucker (LZ) rats for 4 weeks. Blood pressure was measured weekly by tail-cuff method. AT1R functions were determined by measuring diuretic and natriuretic responses to AT1R antagonist (candesartan; 10 ?g/kg/min iv). The mRNA and protein levels of NF-?B, oxidative stress maker and AT1R were determined using quantitative real-time PCR and Western blotting, respectively. The NF-?B-DNA binding activity in renal cortex was measured by Electrophoretic mobility shift assay (EMSA).As compared with LZ rats, ZDF rats had higher blood pressure, impaired natriuresis and diuresis, accompanied with higher levels of oxidative stress and inflammation. Furthermore, AT1R expression was higher in renal cortex from ZDF rats; candesartan induced natriresis and diuresis, which was augmented in ZDF rats. Treatment with PDTC lowered blood pressure and improved diuretic and natriuretic effects in ZDF rats; meanwhile, the increased oxidative stress and inflammation were reduced; the increased AT1R expression and augmented candesartan-mediated natriuresis and diuresis were recoverd in ZDF rats. Our further study investigated the mechanisms of PDTC on AT1R receptor expression. It resulted that PDTC inhibited NF-?B translocation from cytosol to nucleus, inhibited binding of NF-?B with AT1R promoter, therefore, reduced AT1R expression and function.Our present study indicates blockade of NF-?B, via inhibition of binding of NF-?B with AT1R promoter, reduces renal AT1R expression and function, improves oxidative stress and inflammatory/anti-inflammatory balance, therefore, lowers blood pressure and recovers renal function in ZDF rats.

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

Publications

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

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