Yagi K, Kim S, Wanibuchi H, Yamashita T, Yamamura Y, Iwao H
Department of Pharmacology, Osaka City University Medical School, Abeno, Japan.
Hypertension. 1997 Mar;29(3):728-35. doi: 10.1161/01.hyp.29.3.728.
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-beta1 (TGF-beta1) 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 beta-myosin heavy chain (MHC) mRNA of OLETF was increased at 30 and 54 weeks of age, whereas alpha-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-beta1 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 beta- and alpha-MHC expressions seems to participate in the decreased cardiac contractility seen in diabetes. Furthermore, TGF-beta1 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.
为了阐明非胰岛素依赖型糖尿病（NIDDM）中心脏和肾脏并发症的分子机制，我们检测了大冢长-艾氏-德岛肥胖（OLETF）大鼠（一种人类NIDDM的新动物模型）在14周龄（糖尿病前期）、30周龄（NIDDM期）和54周龄（IDDM期）时的基因表达。通过Northern印迹分析测量组织mRNA水平。与对照大鼠（大冢长-艾氏-德岛大鼠）相比，14周龄的OLETF大鼠心脏中转化生长因子-β1（TGF-β1）和细胞外基质（包括I、III和IV型胶原蛋白以及层粘连蛋白）的mRNA显著增加。OLETF大鼠的心脏β-肌球蛋白重链（MHC）mRNA在30周龄和54周龄时增加，而OLETF大鼠的α-MHC mRNA在54周龄时则呈相反下降。从30周龄起，在OLETF大鼠心脏中可见明显的血管周围纤维化。在OLETF大鼠的肾脏中，肾小球TGF-β1表达在30周龄时暂时增加，随后出现以系膜增生、基底膜增厚和结节性病变为特征的肾小球硬化。从糖尿病前期到IDDM期，OLETF大鼠的血压一直高于对照大鼠。因此，在OLETF大鼠中，糖尿病前期心脏纤维化相关基因表达就已增强，这支持了这些基因表达参与心脏血管周围纤维化。β-和α-MHC表达的相反变化似乎参与了糖尿病时心脏收缩力的下降。此外，TGF-β1也可能导致OLETF大鼠的肾小球硬化。OLETF大鼠似乎是研究NIDDM中高血压以及心脏和肾脏并发症机制的有用模型。
