Macrophage-derived tumor necrosis factor-α mediates diabetic renal injury

Monocyte/macrophage recruitment correlates strongly with the progression of diabetic nephropathy. Tumor necrosis factor-α (TNF-α) is produced by monocytes/macrophages but the direct role of TNF-α and/or macrophage-derived TNF-α in the progression of diabetic nephropathy remains unclear. Here we test...

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Veröffentlicht in:Kidney international Jg. 88; H. 4; S. 722 - 733
Hauptverfasser: Awad, Alaa S., You, Hanning, Gao, Ting, Cooper, Timothy K., Nedospasov, Sergei A., Vacher, Jean, Wilkinson, Patrick F., Farrell, Francis X., Brian Reeves, W.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 01.10.2015
Schlagworte:
albuminuria
Albuminuria - genetics
Albuminuria - metabolism
Albuminuria - prevention & control
Animals
Antibodies, Neutralizing - pharmacology
Biomarkers - blood
Blood Urea Nitrogen
CD11b Antigen - genetics
CD11b Antigen - metabolism
Chemotaxis
Creatinine - blood
Diabetes Mellitus, Experimental - complications
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Experimental - metabolism
Diabetic Nephropathies - genetics
Diabetic Nephropathies - metabolism
Diabetic Nephropathies - pathology
Diabetic Nephropathies - prevention & control
diabetic nephropathy
Genetic Predisposition to Disease
inflammation
Inflammation Mediators - antagonists & inhibitors
Inflammation Mediators - metabolism
Kidney - drug effects
Kidney - metabolism
Kidney - pathology
Macrophages, Peritoneal - drug effects
Macrophages, Peritoneal - metabolism
Macrophages, Peritoneal - pathology
Male
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Phenotype
Receptors, Tumor Necrosis Factor, Type I - metabolism
Receptors, Tumor Necrosis Factor, Type II - metabolism
Signal Transduction
Tumor Necrosis Factor-alpha - antagonists & inhibitors
Tumor Necrosis Factor-alpha - deficiency
Tumor Necrosis Factor-alpha - genetics
Tumor Necrosis Factor-alpha - metabolism
albuminuria
inflammation
diabetic nephropathy
ISSN:0085-2538, 1523-1755, 1523-1755
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Zusammenfassung:Monocyte/macrophage recruitment correlates strongly with the progression of diabetic nephropathy. Tumor necrosis factor-α (TNF-α) is produced by monocytes/macrophages but the direct role of TNF-α and/or macrophage-derived TNF-α in the progression of diabetic nephropathy remains unclear. Here we tested whether inhibition of TNF-α confers kidney protection in diabetic nephropathy via a macrophage-derived TNF-α-dependent pathway. Compared to vehicle-treated mice, blockade of TNF-α with a murine anti-TNF-α antibody conferred kidney protection in Ins2Akita mice as indicated by reductions in albuminuria, plasma creatinine, histopathologic changes, kidney macrophage recruitment, and plasma inflammatory cytokine levels at 18 weeks of age. To assess the direct role of macrophage-derived TNF-α in diabetic nephropathy, we generated macrophage-specific TNF-α-deficient mice (CD11bCre/TNF-αFlox/Flox). Conditional ablation of TNF-α in macrophages significantly reduced albuminuria, the increase in plasma creatinine and blood urea nitrogen, histopathologic changes, and kidney macrophage recruitment compared to diabetic TNF-αFlox/Flox control mice after 12 weeks of streptozotocin-induced diabetes. Thus, production of TNF-α by macrophages plays a major role in diabetic renal injury. Hence, blocking TNF-α could be a novel therapeutic approach for treatment of diabetic nephropathy.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0085-2538
1523-1755
1523-1755
DOI:10.1038/ki.2015.162