Yonsei Med J.  2007 Apr;48(2):301-307. 10.3349/ymj.2007.48.2.301.

Beneficial Effects of Thiazolidinediones on Diabetic Nephropathy in OLETF Rats

• Lee MY
• Lee EY
• Lee BJ
• Won CS
• Koh JH
• Shin JY
• Shin YG
• Cho BP
• Chung CH

• KMID: 1779535
• DOI: http://doi.org/10.3349/ymj.2007.48.2.301

Abstract

PURPOSE
Diabetic nephropathy is the most serious of complications in diabetes mellitus. Thiazolidinedione (TZD) is thought to ameliorate diabetic nephropathy; however, the mechanism underlying this effect has not been elucidated. We hypothesized that the vascular endothelial growth factor (VEGF) participates in the pathogenesis of diabetic nephropathy and that TZD may be beneficial for the treatment of diabetic nephropathy because of the effect it has on VEGF. MATERIALS AND METHODS: 23 Otsuka- Long-Evans-Tokushima-Fatty (OLETF) rats and eight control Long-Evans-Tokushima-Otsuka (LETO) rats were divided into the following four groups: LETO group, control OLETF group, pioglitazone treated group (10mg/kg/day), and rosiglitazone treated group (3mg/kg/day). RESULTS: A progressive increase in urinary protein excretion was observed in the diabetic rats. Glomerular VEGF expression in the control OLETF rats was significantly higher than in the control LETO rats. However, there was a significant reduction in both the glomerular VEGF expression and the VEGF mRNA levels after treatment with pioglitazone and rosiglitazone. The twenty-four hour urine protein levels were significantly decreased in both groups of the treated OLETF rats. CONCLUSION: These results suggest that TZD may have beneficial effects on diabetic nephropathy by reducing the VEGF expression.

Keyword

Diabetes mellitus; diabetic nephropathy; thiazolidinediones; vascular endothelial growth factor

MeSH Terms

Vascular Endothelial Growth Factor A/genetics
Thiazolidinediones/*therapeutic use
Rats, Long-Evans
Rats
Male
Hypoglycemic Agents/therapeutic use
Disease Models, Animal
Diabetic Nephropathies/*drug therapy
Diabetes Mellitus, Type 2/*drug therapy
Animals

Figure

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  Fig. 1 Hematoxylin and eosin staining of the glomeruli from LETO rats (A), control OLETF rats (B), pioglitazone treated OLETF rats (C), and rosiglitazone treated OLETF rats (D). Scale bar, 100 µm. The glomerular expansions were observed in the control OLETF rats.

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  Fig. 2 Changes in the glomerular volumes. The glomerular volumes of the control OLETF rats were significantly increased when compared with the LETO rats. After treatment with pioglitazone and rosiglitazone, the glomerular volumes significantly decreased in the control OLETF rats. [PC6]*p < 0.05 vs. control OLETF.

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  Fig. 3 Immunohistochemical stain for glomerular VEGF from LETO rats (A), control OLETF rats (B), pioglitazone treated OLETF (C), and rosiglitazone treated OLETF (D). Scale bar, 100 µm. In the control OLETF rats, the brown pigmentation was darker than in the other groups.

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  Fig. 4 Changes in the optical density of the glomerular VEGF immunoreactivity. Compared with LETO rats, glomerular VEGF expression of the control OLETF rats was significantly increased. Glomerular VEGF expression was significantly decreased when compared to the control OLETF group after treatment with pioglitazone and rosiglitazone. *p < 0.05 vs. control OLETF.

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  Fig. 5 Comparison of the glomerular VEGF mRNA expression. The expected lengths of the PCR products are 330 base pairs (bp) for VEGF120, 462bp for VEGF164, and 514bp for VEGF188. The mRNA expressions of VEGF isoforms (VEGF120, VEGF164, and VEGF188) were significantly increased in the control OLETF rats when compared to the expression levels in the LETO rats. After treatment with pioglitazone and rosiglitazone, the levels of VEGF isoforms decreased to levels observed in LETO rats. Expression of β2-MG was identified at nearly constant levels.

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