Renal pro-inflammatory cytokine gene expression in diabetic nephropathy: effect of angiotensin-converting enzyme inhibition and pentoxifylline administration

Am J Nephrol. 2006;26(6):562-70. doi: 10.1159/000098004. Epub 2006 Dec 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / drug therapy
  • Albuminuria / metabolism
  • Angiotensin-Converting Enzyme Inhibitors / pharmacology*
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Cytokines / drug effects
  • Cytokines / metabolism*
  • Diabetic Nephropathies / chemically induced
  • Diabetic Nephropathies / metabolism*
  • Gene Expression / drug effects
  • Hematologic Agents / pharmacology*
  • Interleukin-1 / metabolism
  • Interleukin-6 / metabolism
  • Kidney / metabolism
  • Male
  • Pentoxifylline / pharmacology*
  • Pentoxifylline / therapeutic use
  • Rats
  • Rats, Sprague-Dawley
  • Streptozocin
  • Tumor Necrosis Factor-alpha / metabolism


  • Angiotensin-Converting Enzyme Inhibitors
  • Cytokines
  • Hematologic Agents
  • Interleukin-1
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Streptozocin
  • Pentoxifylline