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

Monocyte/macrophage recruitment correlates strongly with the progression of diabetic nephropathy. Tumor necrosis factor-alpha (TNF-alpha) is produced by monocytes/macrophages but the direct role of TNF-alpha and/or macrophage-derived TNF-alpha in the progression of diabetic nephropathy remains unclear. Here we tested whether inhibition of TNF-alpha confers kidney protection in diabetic nephropathy via a macrophage-derived TNF-alpha-dependent pathway. Compared to vehicle-treated mice, blockade of TNF-alpha with a murine anti-TNF-alpha 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-alpha in diabetic nephropathy, we generated macrophage-specific TNF-alpha-deficient mice (CD11bCre/TNF-alpha(Flox/Flox)). Conditional ablation of TNF-alpha in macrophages significantly reduced albuminuria, the increase in plasma creatinine and blood urea nitrogen, histopathologic changes, and kidney macrophage recruitment compared to diabetic TNF-alpha(Flox/Flox) control mice after 12 weeks of streptozotocin-induced diabetes. Thus, production of TNF-alpha by macrophages plays a major role in diabetic renal injury. Hence, blocking TNF-alpha could be a novel therapeutic approach for treatment of diabetic nephropathy.