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

Abstract

Background: Recent studies have shown a role for inflammation in the pathogenesis of diabetic nephropathy (DN). Tumor necrosis factor (TNF)-α, 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-α, 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-α, 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-α and IL-6. Both EN and PTF administration virtually abrogated the overexpression of TNF-α, 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-α, 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.

HSP27/HSPB1 as an adaptive podocyte antiapoptotic protein activated by high glucose and angiotensin II

“…Further studies should explore whether HSPB1 might also regulate additional proinflammatory actions of Ang II. 68 In conclusion, HSPB1 is upregulated in vivo and in cultured podocytes by high glucose and Ang II. This appears to be an adaptive response that allows podocytes to cope with these stressors and prevents apoptosis because depletion of this upregulated HSPB1 sensitized to these same stimuli.…”

Circulating TNF Receptors 1 and 2 Predict ESRD in Type 2 Diabetes

“…One is that their elevated concentrations are a manifestation of a disease process present in the kidneys that leads to ESRD. 17 This possibility is made unlikely by the prospective study design and by their strong effect in patients regardless of proteinuria status.…”

“…The criteria were published previously. 16,17,27 In 2009, plasma creatinine was measured in stored baseline samples at the University of Minnesota with the Roche enzymatic assay (Prod no. 11775685) on a Roche/Hitachi Mod P analyzer.…”

Vitality of Pro-Inflammatory Cytokine, Scavenger Receptor Proteins and Atherosclerotic Plaque Markers in Risk Prediction of Diabetic Nephropathy

“…Cortical mRNA expression of IL-6 is increased in diabetic kidney in comparison with normal rodents and is positively associated with elevated urinary concentrations of albumin (Navarro et al, 2006). Similarly, other researcher published work on interstitial expression of IL-6 mRNA in human renal tissue from individuals with diabetes, correlates with histological features of interstitial injury (Suzuki et al, 1995).…”

“…This mechanism has been proved in the development of kidney injury in patients with T2DM. Moreover, high serum and urinary concentrations of IL-6 are associated with greater albuminuria in patients with DN; however, serum and urinary levels do not correlate with each other (Shikano et al, 2000, andNavarro et al, 2006). IL-10 plays an essential role in the pathogenesis of DN.…”