The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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Phosphodiesterase Inhibitor Improves Renal Tubulointerstitial Hypoxia of the Diabetic Rat Kidney

  • Sun, Hui-Kyoung (Division of Nephrology, Department of Internal Medicine, Ilsan-Paik Hospital, Inje University College of Medicine) ;
  • Lee, Yun-Mi (Clinical Research Center, Ilsan-Paik Hospital, Inje University College of Medicine) ;
  • Han, Kum-Hyun (Division of Nephrology, Department of Internal Medicine, Ilsan-Paik Hospital, Inje University College of Medicine) ;
  • Kim, Han-Seong (Department of Pathology, Ilsan-Paik Hospital, Inje University College of Medicine) ;
  • Ahn, Seon-Ho (Division of Nephrology, Department of Medicine, Wonkwang University College of Medicine) ;
  • Han, Sang-Youb (Division of Nephrology, Department of Internal Medicine, Ilsan-Paik Hospital, Inje University College of Medicine)
  • Published : 2012.06.01
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Abstract

Background/Aims: Renal hypoxia is involved in the pathogenesis of diabetic nephropathy. Pentoxifyllin (PTX), a non-selective phosphodiesterase inhibitor, is used to attenuate peripheral vascular diseases. To determine whether PTX can improve renal hypoxia, we investigated its effect in the streptozocin (STZ)-induced diabetic kidney. Methods: PTX (40 mg/kg, PO) was administered to STZ-induced diabetic rats for 8 weeks. To determine tissue hypoxia, we examined hypoxic inducible factor-$1{\alpha}$ (HIF-$1{\alpha}$), heme oxygenase-1 (HO-1), vascular endothelial growth factor (VEGF), and glucose transporter-1 (GLUT-1) levels. We also tested the effect of PTX on HIF-$1{\alpha}$ in renal tubule cells. Results: PTX reduced the increased protein creatinine ratio in diabetic rats at 8 weeks. HIF-$1{\alpha}$, VEGF, and GLUT-1 mRNA expression increased significantly, and the expression of HO-1 also tended to increase in diabetic rats. PTX significantly decreased mRNA expression of HIF-$1{\alpha}$ and VEGF at 4 and 8 weeks, and decreased HO-1 and GLUT-1 at 4 weeks. The expression of HIF-$1{\alpha}$ protein was significantly increased at 4 and 8 weeks in tubules in the diabetic rat kidney. PTX tended to decrease HIF-$1{\alpha}$ protein expression at 8 weeks. To examine whether PTX had a direct effect on renal tubules, normal rat kidney cells were stimulated with $CoCl_{2}$ (100 ${\mu}m$), which enhanced HIF-$1{\alpha}$ mRNA and protein levels under low glucose conditions (5.5 mM). Their expressions were similar even after high glucose (30 mM) treatment. PTX had no effect on HIF-$1{\alpha}$ expression. Conclusions: PTX attenuates tubular hypoxia in the diabetic kidney.

Keywords

References

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