Yonsei Med J.  2010 May;51(3):385-391. 10.3349/ymj.2010.51.3.385.

Aldose Reductase Inhibitor Ameliorates Renal Vascular Endothelial Growth Factor Expression in Streptozotocin-Induced Diabetic Rats

• Sung JK
• Koh JH
• Lee MY
• Kim BH
• Nam SM
• Kim JH
• Yoo JH
• Kim SH
• Hong SW
• Lee EY
• Choi R
• Chung CH

• KMID: 1074990
• DOI: http://doi.org/10.3349/ymj.2010.51.3.385

Abstract

PURPOSE
The vascular endothelial growth factor (VEGF) expression of podocyte is one of the well-known major factors in development of diabetic nephropathy. In this study, we investigated the effects of aldose reductase inhibitor, fidarestat on diabetic nephropathy, and renal VEGF expression in a type 1 diabetic rat model.
MATERIALS AND METHODS
Twenty four Sprague-Dawley male rats which were performed intraperitoneal injection of streptozotocin and normal six rats were divided into four groups including a normal control group, untreated diabetic control group, aldose reductase (AR) inhibitor (fidarestat, 16 mg.kg(-1).day(-1)) treated diabetic group, and angiotensin receptor blocker (losartan, 20 mg.kg(-1).day(-1)) treated diabetic group. We checked body weights and blood glucose levels monthly and measured urine albumin-creatinine ratio (ACR) at 8 and 32 weeks. We extracted the kidney to examine the renal morphology and VEGF expressions.
RESULTS
The ACR decreased in fidarestat and losartan treated diabetic rat groups than in untreated diabetic group (24.79 +/- 11.12, 16.11 +/- 9.95, and 84.85 +/- 91.19, p < 0.05). The renal VEGF messenger RNA (mRNA) and protein expression were significantly decreased in the fidarestat and losartan treated diabetic rat groups than in the diabetic control group.
CONCLUSION
We suggested that aldose reductase inhibitor may have preventive effect on diabetic nephropathy by reducing renal VEGF overexpression.

Keyword

Aldose reductase inhibitor; vascular endothelial growth factor; albumin creatinine ratio; diabetic nephropathy

MeSH Terms

Aldehyde Reductase/*antagonists & inhibitors
Animals
Antihypertensive Agents/therapeutic use
Diabetes Mellitus, Experimental/*drug therapy/*metabolism
Diabetic Nephropathies/prevention & control
Imidazolidines/*therapeutic use
Kidney/*drug effects/*metabolism/pathology
Losartan/therapeutic use
Male
Rats
Rats, Sprague-Dawley
Receptors, Angiotensin/*antagonists & inhibitors
Vascular Endothelial Growth Factor A

Figure

• 

  Fig. 1 Representative examples of PAS staining of glomeruli are shown for (A) CON, (B) DM, (C) DM + ARI, and (D) DM + ARB. (E) is calculated glomerular volumes at 32nd week. The calculated glomerular volumes did not differ among the experimental groups. Scale bar, 100 µm. CON, control; DM, diabetes; ARI, aldose reductase inhibitor; ARB, angiotensin II receptor blocker.

• 

  Fig. 2 Comparison of glomerular matrix indices (GMI). Although calculated glomerular volumes did not differ among the experimental groups, the glomerular mesangium significantly expanded in untreated diabetic rats compared to the control rats, and it was ameliorated by ARI and ARB treatments. CON, control; DM, diabetes; ARI, aldose reductase inhibitor; ARB, angiotensin II receptor blocker. *p < 0.05 compared with CON, †p < 0.05 compared with DM.

• 

  Fig. 3 Immunohistochemical staining for VEGF from (A) CON, (B) DM, (C) DM + ARI, (D) DM + ARB. Scale bar, 100 µm. (E) is optical density of the glomerular VEGF. The optical density of immunohistochemical staining for VEGF in the diabetic control group increased significantly compared to the normal control group. Furthermore, the ARI and ARB treated diabetic groups had significantly lower expression of VEGF than the diabetic control group. *p < 0.05 compared with CON, †p < 0.05 compared with DM. VEGF, vascular endothelial growth factor; CON, control; DM, diabetes; ARI, aldose reductase inhibitor; ARB, angiotensin II receptor blocker.

• 

  Fig. 4 Quantification of renal VEGF mRNA by real time RT-PCR. The VEGF / GAPDH ratio in the diabetic control group increased compared to the normal control rats. Treatment with ARI decreased VEGF mRNA expression. In addition, the ARB treated diabetic group decreased VEGF mRNA expression. However, there were no significant differences in VEGF mRNA expression between the ARI and ARB treated diabetic groups. *p < 0.05 compared with CON, †p < 0.05 compared with DM. VEGF, vascular endothelial growth factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; mRNA, messenger RNA; RT-PCR, reverse transcriptase-polymerase chain reaction; CON, control; DM, diabetes; ARI, aldose reductase inhibitor; ARB, angiotensin II receptor blocker.

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