title: Macrophage-derived tumor necrosis factor-α mediates diabetic renal injury.
abstract: 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 Ins2(Akita) 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 (CD11b(Cre)/TNF-α(Flox/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-α(Flox/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.
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Alaa S
authors.initials: AS
authors.lastname: Awad
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Hanning
authors.initials: H
authors.lastname: You
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Gao
authors.affiliation: Department of Comparative Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.affiliation: Engelhardt Institute of Molecular Biology and Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Nedospasov
authors.affiliation: Clinical Research Institute of Montreal, Départment de Médecine, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Vacher
authors.affiliation: Department of Immunology Research, Janssen R&D, Spring House, Pennsylvania, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Wilkinson
authors.affiliation: Department of Immunology Research, Janssen R&D, Spring House, Pennsylvania, USA.
authors.forename: Francis X
authors.initials: FX
authors.lastname: Farrell
authors.affiliation: Department of Medicine, Penn State University College of Medicine, Hershey, Pennsylvania, USA.
authors.forename: W
authors.initials: W
authors.lastname: Brian Reeves
mesh_terms: D000419:Albuminuria / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001806:Blood Urea Nitrogen; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis; D003404:Creatinine / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020022:Genetic Predisposition to Disease; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010641:Phenotype; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D015415:Biomarkers; D039481:CD11b Antigen; D018836:Inflammation Mediators; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine