Korean J Intern Med.  2012 Jun;27(2):163-170. 10.3904/kjim.2012.27.2.163.

Phosphodiesterase Inhibitor Improves Renal Tubulointerstitial Hypoxia of the Diabetic Rat Kidney

• Sun HK
• Lee YM
• Han KH
• Kim HS
• Ahn SH
• Han SY

• KMID: 1776543
• DOI: http://doi.org/10.3904/kjim.2012.27.2.163

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.

Keyword

Cell hypoxia; Diabetic nephropathies; Phosphodiesterase inhibitors

MeSH Terms

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