Phosphodiesterase Inhibitor Improves Renal Tubulointerstitial Hypoxia of the Diabetic Rat Kidney

Abstract

Background/AimsRenal 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.MethodsPTX (40 mg/kg, PO) 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.ResultsPTX 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 CoCl2 (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.ConclusionsPTX attenuates tubular hypoxia in the diabetic kidney.

Effects and clinical significance of pentoxifylline on the oxidative stress of rats with diabetic nephropathy

“…Our study showed urinary protein excretion of the rats was significantly decreased after PTX treatment and the effect of higher dose of PTX was better than that of low-dose PTX or benazepril. These findings were consistent with those reported in the previous studies [3, [14][15][16][17] . With pathological methods, we proved that PTX was able to alleviate renal tissue damages of DN rats.…”

Ameliorative effects of pentoxifylline on NOS induced by diabetes in rat kidney

“…35 Similarly, in another study, a decrease in HIF-1a and VEGF expression in the kidney of diabetic rats was shown. 36 However, the effect of PTX on NOS has not been investigated in the diabetic kidney so far. In the present study, we demonstrated that PTX ameliorated eNOS, iNOS and nNOS protein levels, but did not affect mRNA levels.…”

Effect of Pentoxifylline on Renal Function and Urinary Albumin Excretion in Patients with Diabetic Kidney Disease

“…32 There is a strong biologic rationale for inflammation, oxidative stress, and fibrosis, to be critical risk factors for renal disease progression in DKD. [33][34][35] Experimental research has shown that PTF diminishes renal tissue damage through beneficial anti-inflammatory, antioxidant, and antifibrotic effects, 17,36,37 resulting in attenuation of kidney disease progression. This outcome is maximized after combination with RAS blockers.…”

“…All patients were white, with a mean age of 69.869.2 years, a similar distribution by sex (53.8% men and 46.2% women), and a mean duration of diabetes of 1563.4 years. The mean baseline eGFR was 37 (Figure 2). Likewise, glycemic control did not differ between groups during follow-up.…”