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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Vydáno v:	Kidney international Ročník 88; číslo 4; s. 722 - 733
Hlavní autoři:	Awad, Alaa S., You, Hanning, Gao, Ting, Cooper, Timothy K., Nedospasov, Sergei A., Vacher, Jean, Wilkinson, Patrick F., Farrell, Francis X., Brian Reeves, W.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Elsevier Inc 01.10.2015
Témata:	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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Popis
Shrnutí:	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.
Bibliografie:	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