Phosphodiesterase inhibitor improves renal tubulointerstitial hypoxia of the diabetic rat kidney.
OBJECTIVE
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.
Division of Nephrology, Department of Internal Medicine, Ilsan-Paik Hospital, Inje University College of Medicine, Goyang, Korea.
Hui-Kyoung
HK
Sun
Yun Mi
YM
Lee
Kum Hyun
KH
Han
Han-Seong
HS
Kim
Seon-Ho
SH
Ahn
Sang-Youb
SY
Han
D000818:Animals; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000235:genetics; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D051272:Glucose Transporter Type 1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; C495679:Slc2a1 protein, rat; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D003035:Cobalt; D013311:Streptozocin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C018021:cobaltous chloride; D005947:Glucose; D010431:Pentoxifylline