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.


CONCLUSIONS
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.
Navarro
Juan F
JF
Nephrology Service, University Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain. jnavgon@gobiernodecanarias.org
Milena
Francisco J
FJ
Mora
Carmen
C
León
Candelaria
C
García
Javier
J
D000419:Albuminuria / Q000188:drug therapy / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006401:Hematologic Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D010431:Pentoxifylline / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D016207:Cytokines; D006401:Hematologic Agents; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D013311:Streptozocin; D010431:Pentoxifylline