Previously it was shown that the TNF superfamily member TWEAK (TNFSF12) acts through its
receptor, Fn14, to promote proinflammatory responses in kidney cells, including the production of MCP-1,
RANTES, IP-10 and KC. In addition, the TWEAK/Fn14 pathway promotes mesangial cell proliferation, vascular cell activation, and renal cell death. To study the relevance of the TWEAK/Fn14 pathway in the pathogenesis of antibody-induced
nephritis using the mouse model of nephrotoxic serum
nephritis (NTN), we induced NTN by passive transfer of rabbit anti-glomerular
antibodies into Fn14 knockout (KO) and wild type (WT) mice. Severe
proteinuria as well as renal histopathology were induced in WT but not in Fn14 KO mice. Similarly, a pharmacologic approach of anti-TWEAK mAb administration into WT mice in the NTN model significantly ameliorated
proteinuria and improved kidney histology. Anti-TWEAK treatment did not affect the generation of mouse anti-rabbit
antibodies; however, within the kidney there was a significant decrease in glomerular
immunoglobulin deposition, as well as macrophage infiltrates and tubulointerstitial
fibrosis. The mechanism of action is most likely due to reductions in downstream targets of TWEAK/Fn14 signaling, including reduced renal expression of MCP-1,
VCAM-1, IP-10,
RANTES as well as Fn14 itself, and other molecular pathways associated with
fibrosis in anti-TWEAK treated mice. Thus, TWEAK/Fn14 interactions are instrumental in the pathogenesis of
nephritis in the NTN model, apparently mediating a cascade of pathologic events locally in the kidney rather than by impacting the systemic immune response. Disrupting TWEAK/Fn14 interactions may be an innovative kidney-protective approach for the treatment of
lupus nephritis and other antibody-induced renal diseases.