Renal Pro-Inflammatory Cytokine Gene Expression in Diabetic Nephropathy: Effect of Angiotensin-Converting Enzyme Inhibition and Pentoxifylline Administration

BACKGROUND: Recent studies have shown a role for inflammation in the pathogenesis of diabetic nephropathy (DN). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 and IL-6 are cytokines with a prevalent pro-inflammatory activity. Our objective was to study the renal gene expression of TNF-alpha, IL-1 and IL-6 in DN and their relationship with renal damage assessed by urinary albumin excretion (UAE). In addition, we also investigated the effect of angiotensin-converting enzyme inhibition and pentoxifylline (PTF) administration on these parameters. METHODS: After streptozotocin-induced diabetes, rats received either no treatment or therapy with enalapril (EN) or PTF for 8 weeks. Renal expression of pro-inflammatory cytokines was evaluated by real-time polymerase chain reaction. Urinary cytokine excretion and albuminuria were also evaluated. RESULTS: Renal cortical mRNA expression for TNF-alpha, IL-1 and IL-6 in untreated diabetic rats was 2.4-, 1.2- and 3.4-fold higher than in non-diabetic rats. Kidney weight and UAE were significantly associated with renal mRNA expression of TNF-alpha and IL-6. Both EN and PTF administration virtually abrogated the overexpression of TNF-alpha, IL-1 and IL-6, which was associated with a reduction in kidney weight and urinary albumin excretion. CONCLUSION: The renal expression of the main pro-inflammatory cytokines TNF-alpha, IL-1 and IL-6 is increased in DN, which is significantly associated with UAE. EN and PTF administration prevented this enhanced expression, leading to a decrease in urinary cytokine excretion and a reduction in albuminuria. These findings provide novel insight into the pathogenic mechanisms of DN, supporting the hypothesis that inflammatory mechanisms play a role in the renal injury secondary to diabetes mellitus.