AbstractThe tumour necrosis factor (TNF) family member TWEAK activates the Fn14 receptor and has pro‐apoptotic, proliferative and pro‐inflammatory actions that depend on the cell type and the microenvironment. We explored the proliferative actions of TWEAK on cultured tubular cells and in vivo on renal tubules. Additionally, we studied the role of TWEAK in compensatory proliferation following unilateral nephrectomy and in an inflammatory model of acute kidney injury (AKI) induced by a folic acid overdose. TWEAK increased the proliferation, cell number and cyclin D1 expression of cultured tubular cells, in vitro. Exposure to serum increased TWEAK and Fn14 expression and the proliferative response to TWEAK. TWEAK activated the mitogen‐activated protein kinases ERK and p38, the phosphatidyl‐inositol 3‐kinase (PI3K)/Akt pathway and NF‐κB. TWEAK‐induced proliferation was prevented by inhibitors of these protein kinases and by the NF‐κB inhibitor parthenolide. TWEAK‐induced tubular cell proliferation as assessed by PCNA and cyclin D1 expression in the kidneys of adult healthy mice in vivo. By contrast, TWEAK knock‐out mice displayed lower tubular cell proliferation in the remnant kidney following unilateral nephrectomy, a non‐inflammatory model. This is consistent with TWEAK‐induced proliferation on cultured tubular cells in the absence of inflammatory cytokines. Consistent with our previously published data, in the presence of inflammatory cytokines TWEAK promoted apoptosis, not proliferation, of cultured tubular cells. In this regard, TWEAK knock‐out mice with AKI displayed less tubular apoptosis and proliferation, as well as improved renal function. In conclusion, TWEAK actions in tubular cells are context dependent. In a non‐inflammatory milieu TWEAK induces proliferation of tubular epithelium. This may be relevant for compensatory renal hyperplasia following nephrectomy.