Thiazolidinediones, synthetic ligands of peroxisome proliferator-activated receptor gamma (PPARgamma), are reported to have direct beneficial effects on diabetic nephropathy without lowering blood glucose levels in human and rat. We hypothesized these effects of thiazolidinediones might be derived from PPARgamma activation of kidney cells, and we examined the expression of PPARgamma and the effect of PPARgamma agonists, troglitazone and 15-deoxy-delta-prostaglandin J2 (15d-PGJ2), on the proliferation and differentiation in rat mesangial cells. A single band of mRNA of PPARgamma with a predicted size was detected in reverse transcription-polymerase chain reaction products (RT-PCR) using established PCR probes of PPARgamma. PPARgamma protein in rat mesangial cells was identified as PPARgamma1 by a Western blot. In a gel mobility shift assay to determine a binding activity of PPARgamma, the nuclear protein from rat mesangial cells bound to a (32)P-labeled oligonucleotide probe, including PPAR response elements. A synthetic and a natural ligand of PPARgamma, troglitazone and 15d-PGJ2, decreased thymidine incorporation in a dose dependent manner. After 7 days incubation with troglitazone and 15d-PGJ2, alpha-smooth muscle actin expression, a marker of mesangial cell de-differentiation, was decreased significantly compared to that of control. These results indicate that PPARgamma1 is expressing in rat mesangial cells, and PPARgamma1 activation with its agonists modulates the proliferation and differentiation of cultured rat mesangial cells.

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The present study was designed to develop an animal model of multiple risk factors, including obesity, hypertension, non-insulin-dependent diabetes mellitus, and hyperlipidemia. Hypothalamic obesity was induced by neonatal monosodium glutamate (MSG) treatment in spontaneously hypertensive rats (SHR). Female newborn SHR were treated intraperitoneally with 2 or 4 mg/kg body weight of MSG for 5 days. Obesity developed in SHR treated with 4 mg/kg of MSG but not in SHR treated with 2 mg/kg of MSG. Obese SHR had impaired glucose tolerance, hyperinsulinemia, and hypertriglyceridemia. However, the severity of hypertension was attenuated in obese SHR as compared with control SHR. The degree of obesity was closely related to the metabolic abnormalities, but inversely correlated with the blood pressure level. Macrovascular changes were investigated in obese SHR at 14 months of age. Intimal thickening was accelerated in the carotid artery of obese SHR as compared with that of nonobese SHR. Aortic contents of DNA and total cholesterol were significantly increased in obese SHR. SHR associated with MSG-induced obesity showed major manifestations of metabolic syndrome X. This animal model may be useful to study the clustering of risk factors for the development of macrovascular diseases. (Hypertens Res 1998; 21: 1-6) Key Words: insulin resistance, diabetes mellitus, syndrome X, atherosclerosis, animal model Obesity, hypertension, non-insulin-dependent diabetes mellitus (NIDDM), and hyperlipidemia frequently exist in the same individual, and clustering of these closely related risk factors markedly increases the incidence and prevalence of atherosclerotic diseases (1-7). Insulin resistance and consequent hyperinsulinemia or visceral fat accumulation may play a pathogenetic role in the clustering of risk factors, i. e. , metabolic syndrome X. However, the relationship among these risk factors, especially that between hypertension and other metabolic diseases, is controversial (5-8). Our understanding of metabolic syndrome X may be enhanced by the development of an animal model of this syndrome. We therefore designed the present study to induce experimental obesity in spontaneously hypertensive rats (SHR) by treatment with small or large doses of monosodium glutamate (MSG). MSG induces hypothalamic damage when given during neonatally, leading to stunted growth and obesity (9). We studied the effects of MSG-induced obesity on hypertension, glycemia, lipidemia, and the development of macrovascular changes in the obese SHR. Materials and MethodsSHR were from our inbred colony and were bred in specific-pathogen-free conditions at Kyushu University Animal Center, where both temperature and lighting (on from 8:00 am to 8:00 pm) were controlled. They had free access to tap water and a standard chow diet, which contained 51.6% carbohydrate, 24.8% protein, 7.0% minerals, 4.4% fat, and 3.5% cellulose (flea Japan Inc., Tokyo, Japan). Animals were cared for as directed by guidelines of Kyushu University. Female newborn SHR were treated intrap...

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