The role of TGF-β-activated kinase 1 in db/db mice and high glucose-induced macrophage

•TGF-β-activated kinase 1 (TAK1) signal pathway activates inflammatory response in db/db mice.•TAK1 inhibitor reduces diabetes-induced histological changes and inflammatory cytokines expression in db/db mice.•High glucose stimulates the increased TAK1 signal pathway and MCP-1, TNF-α in macrophages.•Inhibition of TAK1 by 5Z-7-oxozeaenol reduces the inflammatory effects of high glucose-induced macrophages.

Accumulating evidence reveals that inflammation plays a vital part in the development of diabetic nephropathy (DN), little information is available about the TGF-β-activated kinase 1 (TAK1) signal pathway activating inflammatory response in DN. We used bone marrow-derived macrophages (BMMs) and db/db mice to investigate the potential protective effects and mechanisms of TAK1 inhibitor (5Z-7-oxozeaenol) on diabetic kidney disease. The study showed that pretreatment with 5Z-7-oxozeaenol not only remarkably decreased high glucose (HG) stimulated excessive release of MCP-1 and TNF-α, but also significantly down-regulated ERK1/2, p38MAPK phosphorylation, and NF-κB activation in macrophages. In consistent, 5Z-7-oxozeaenol markedly reduced diabetes-induced albuminuria, histological changes, macrophage infiltration, and renal inflammatory cytokines expression and exerted its function through down-regulating ERK1/2, p38MAPK, NF-κB activation in the kidneys of db/db mice. Our findings may provide a novel direction to study the molecular mechanism and a perspective intervention to halt the progression of DN.