TGF-β1-activated kinase-1 regulates inflammation and fibrosis in the obstructed kidney

Activation of c-Jun amino kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and the transcription factor nuclear factor-κB (NF-κB) drives renal inflammation and fibrosis. However, the upstream MAP kinase kinase kinase (MAP3K) enzyme(s) that activate these pathways in kidney disease are unknown. We determined the role of one candidate MAP3K enzyme, transforming growth factor-β1-activated kinase-1 (TAK1/ MAP3K7), in activation of JNK, p38, and NF-κB in the obstructed kidney using conditional gene deletion in adult mice, and assessed the potential protective effect of TAK1 deletion on renal pathology. TAK1 deletion in cultured tubular epithelial cells substantially inhibited IL-1 and TNF-α-induced JNK, p38, and NF-κB signaling and the proinflammatory response. Map3k7(f/f)Cre-ER(TM) mice (in which tamoxifen induces global TAK1 deletion) and control Map3k7(f/f) mice were given tamoxifen at the time of unilateral ureteric obstruction (UUO) and then killed 2, 4, or 5 days later. Tamoxifen-treated control Map3k7(f/f) mice showed the expected activation of JNK, p38, and NF-κB signaling on days 2, 4, and 5, with macrophage infiltration and upregulation of mRNA levels of proinflammatory molecules (IL-1α, TNF-α, NOS2, and CCL2). Control Map3k7(f/f) mice also showed interstitial myofibroblast accumulation and collagen deposition in the obstructed kidney. Tamoxifen treatment of Map3k7(f/f)Cre-ER(TM) mice caused a 60% reduction in renal TAK1 expression on day 4 and >80% on day 5 UUO. Coincident with TAK1 deletion, activation of JNK, p38, and NF-κB signaling was markedly suppressed on days 4 to 5 UUO, which halted renal macrophage accumulation and expression of proinflammatory molecules. TAK1 deletion also halted the development of renal fibrosis in terms of myofibroblast accumulation, collagen deposition, and expression of profibrotic molecules. In conclusion, these studies establish TAK1 as a major upstream activator of JNK, p38, and NF-κB signaling in the obstructed kidney, and they define a pathologic role for TAK1 in renal inflammation and fibrosis.