Masakuni Noda1,*, Takanori Matsuo1, Hiroko Nagano-Tsuge1, Masayuki Ohta2, Masahiro Sekiguchi3, Yumiko Shibouta4, Takehiko Naka5 and Yoshimi Imura1
1Pharmacology Research Laboratories II, 3Drug Analysis & Pharmacokinetics Research Laboratories, 4Research Management Department and 5Medical Chemistry Research Laboratories, Pharmaceutical Research Division, and 2Pharmaceutical Discovery Research Division, Takeda Chemical Industries, Ltd., Osaka 532-8686, Japan
*Corresponding author. FAX: +81-6-6300-6306, E-mail: Noda_Masakuni@takeda.co.jp
Abstract: Wistar fatty (WF) rats have a genetic predisposition to hyperglycemia, polyuria, hyperinsulinemia, hyperlipidemia, obesity and nephropathy. These phenotypic characteristics are similar to those observed in obese patients with non-insulin-dependent diabetes mellitus (NIDDM) nephropathy. In this study, the effects of two types of renin-angiotensin system inhibitors, an angiotensin II type 1-receptor antagonist (AT1A) and an angiotensin I-converting enzyme inhibitor (ACEI), on renal injury in WF rats were studied during the progressive phase of diabetic nephropathy. An AT1A, candesartan cilexetil (1 mg/kg), and an ACEI, enalapril (10 mg/kg), were administered orally once a day for 12 weeks, beginning when the rats were 27-week-old and already showed diabetic nephropathy and obesity. Both drugs prevented an increase in proteinuria during the experimental period. Furthermore, after 4-week intervention, the levels of proteinuria were markedly lower in drug-treated rats. At the end of the experiment, both drugs prevented the development of glomerular lesions without affecting glucose metabolism and obesity. In conclusion, the inhibition of angiotensin II activity ameliorated both existing proteinuria and the progression of proteinuria, resulting in preservation of glomerular structure. Thus angiotensin II plays important roles in the development and the progression of nephropathy in genetically obese diabetic WF rats.
Keywords: Renin-angiotensin system, Angiotensin II-receptor antagonist, Candesartan cilexetil, Non-insulin-dependent diabetes mellitus, Nephropathy
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