Characteristics of Diabetes, Blood Pressure, and Cardiac and Renal Complications in Otsuka Long-Evans Tokushima Fatty Rats

To characterize the molecular mechanism of cardiac and renal complications in non–insulin-dependent diabetes mellitus (NIDDM), we examined the gene expression of Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a new animal model for human NIDDM, at the ages of 14 weeks (prediabetic stage), 30 weeks (NIDDM stage), and 54 weeks (IDDM stage). Tissue mRNA levels were measured by Northern blot analysis. In 14-week-old OLETF rats, cardiac mRNAs for transforming growth factor-β1 (TGF-β1) and extracellular matrix, including collagen types I, III, and IV and laminin, were significantly increased compared with control rats (Long-Evans Tokushima Otsuka rats). Cardiac β-myosin heavy chain (MHC) mRNA of OLETF was increased at 30 and 54 weeks of age, whereas α-MHC mRNA of OLETF was inversely decreased at 54 weeks. Marked perivascular fibrosis was seen in the hearts of OLETF rats from 30 weeks of age. In the kidney of OLETF rats, glomerular TGF-β1 expression was temporally increased at 30 weeks of age, followed by glomerulosclerosis characterized by mesangial proliferation, thickening of the basement membrane, and nodular lesions. Blood pressure of OLETF rats remained higher than that of control rats from the prediabetic stage to the IDDM stage. Thus, in OLETF rats, cardiac fibrosis–related gene expressions were already enhanced at the prediabetic stage, which supports the involvement of these gene expressions in cardiac perivascular fibrosis. The antithetical change in β- and α-MHC expressions seems to participate in the decreased cardiac contractility seen in diabetes. Furthermore, TGF-β1 may also contribute to glomerulosclerosis of OLETF rats. OLETF rats seem to be a useful model to study the mechanism of hypertension and cardiac and renal complications in NIDDM.