Phosphodiesterase Inhibitor Improves Renal Tubulointerstitial Hypoxia of the Diabetic Rat Kidney.
10.3904/kjim.2012.27.2.163
- Author:
Hui Kyoung SUN
1
;
Yun Mi LEE
;
Kum Hyun HAN
;
Han Seong KIM
;
Seon Ho AHN
;
Sang Youb HAN
Author Information
1. Division of Nephrology, Department of Internal Medicine, Ilsan-Paik Hospital, Inje University College of Medicine, Goyang, Korea. hansy@paik.ac.kr
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
Cell hypoxia;
Diabetic nephropathies;
Phosphodiesterase inhibitors
- MeSH:
Animals;
Anoxia/*drug therapy/enzymology/etiology/genetics;
Cell Line;
Cobalt/pharmacology;
Diabetes Mellitus, Experimental/*complications;
Diabetic Nephropathies/*drug therapy/enzymology/etiology/genetics;
Disease Models, Animal;
Gene Expression Regulation/drug effects;
Glucose/metabolism;
Glucose Transporter Type 1/genetics;
Heme Oxygenase (Decyclizing)/genetics/metabolism;
Hypoxia-Inducible Factor 1, alpha Subunit/genetics/metabolism;
Kidney Tubules/*drug effects/enzymology;
Male;
Pentoxifylline/*pharmacology;
Phosphodiesterase Inhibitors/*pharmacology;
RNA, Messenger/metabolism;
Rats;
Rats, Sprague-Dawley;
Streptozocin;
Time Factors;
Vascular Endothelial Growth Factor A/genetics
- From:The Korean Journal of Internal Medicine
2012;27(2):163-170
- CountryRepublic of Korea
- Language:English
-
Abstract:
BACKGROUND/AIMS: Renal hypoxia is involved in the pathogenesis of diabetic nephropathy. Pentoxifyllin (PTX), a nonselective 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-1alpha (HIF-1alpha), 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-1alpha in renal tubule cells. RESULTS: PTX reduced the increased protein creatinine ratio in diabetic rats at 8 weeks. HIF-1alpha, 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-1alpha and VEGF at 4 and 8 weeks, and decreased HO-1 and GLUT-1 at 4 weeks. The expression of HIF-1alpha protein was significantly increased at 4 and 8 weeks in tubules in the diabetic rat kidney. PTX tended to decrease HIF-1alpha protein expression at 8 weeks. To examine whether PTX had a direct effect on renal tubules, normal rat kidney cells were stimulated with CoCl2 (100 microM), which enhanced HIF-1alpha 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-1alpha expression. CONCLUSIONS: PTX attenuates tubular hypoxia in the diabetic kidney.
