TY - JOUR
T1 - Macrophage-derived tumor necrosis factor-α mediates diabetic renal injury
AU - Awad, Alaa S.
AU - You, Hanning
AU - Gao, Ting
AU - Cooper, Timothy K.
AU - Nedospasov, Sergei A.
AU - Vacher, Jean
AU - Wilkinson, Patrick F.
AU - Farrell, Francis X.
AU - Brian Reeves, W.
N1 - Funding Information:
This study was supported by NIH grants DK094930 and DK094930S1 (to ASA) and DK081876 (to WBR) and a grant from Johnson and Johnson.
Funding Information:
Portions of this work were supported by a grant from Johnson and Johnson that markets a TNF-α antagonist. At the time of the study, PFW and FXF were employees of Janssen R&D, a subsidiary of Johnson and Johnson. All the authors declared no competing interests.
PY - 2015/10/3
Y1 - 2015/10/3
N2 - 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.
AB - 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.
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U2 - 10.1038/ki.2015.162
DO - 10.1038/ki.2015.162
M3 - Article
C2 - 26061548
AN - SCOPUS:84942985729
SN - 0085-2538
VL - 88
SP - 722
EP - 733
JO - Kidney International
JF - Kidney International
IS - 4
ER -
