Phosphodiesterase inhibitor improves renal tubulointerstitial hypoxia of the diabetic rat kidney

Korean J Intern Med. 2012 Jun;27(2):163-70. doi: 10.3904/kjim.2012.27.2.163. Epub 2012 May 31.


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, p.o.) was administered to STZ-induced diabetic rats for 8 weeks. To determine tissue hypoxia, we examined hypoxic inducible factor-1α (HIF-1α), 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-1α in renal tubule cells.

Results: PTX reduced the increased protein creatinine ratio in diabetic rats at 8 weeks. HIF-1α, 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-1α and VEGF at 4 and 8 weeks, and decreased HO-1 and GLUT-1 at 4 weeks. The expression of HIF-1α protein was significantly increased at 4 and 8 weeks in tubules in the diabetic rat kidney. PTX tended to decrease HIF-1α 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 µM), which enhanced HIF-1α 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-1α expression.

Conclusions: PTX attenuates tubular hypoxia in the diabetic kidney.

Keywords: Cell hypoxia; Diabetic nephropathies; Phosphodiesterase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cobalt / pharmacology
  • Diabetes Mellitus, Experimental / complications*
  • Diabetic Nephropathies / drug therapy*
  • Diabetic Nephropathies / enzymology
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / genetics
  • Disease Models, Animal
  • Gene Expression Regulation / drug effects
  • Glucose / metabolism
  • Glucose Transporter Type 1 / genetics
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism
  • Hypoxia / drug therapy*
  • Hypoxia / enzymology
  • Hypoxia / etiology
  • Hypoxia / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Kidney Tubules / drug effects*
  • Kidney Tubules / enzymology
  • Male
  • Pentoxifylline / pharmacology*
  • Phosphodiesterase Inhibitors / pharmacology*
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Streptozocin
  • Time Factors
  • Vascular Endothelial Growth Factor A / genetics


  • Glucose Transporter Type 1
  • Hif1a protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Phosphodiesterase Inhibitors
  • RNA, Messenger
  • Slc2a1 protein, rat
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, rat
  • Cobalt
  • Streptozocin
  • Heme Oxygenase (Decyclizing)
  • Hmox1 protein, rat
  • cobaltous chloride
  • Glucose
  • Pentoxifylline