title: Inhibition of the TWEAK/Fn14 pathway attenuates renal disease in nephrotoxic serum nephritis.
abstract: 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.
authors.affiliation: Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Xia
authors.forename: Sean R
authors.initials: SR
authors.lastname: Campbell
authors.forename: Anna
authors.initials: A
authors.lastname: Broder
authors.forename: Leal
authors.initials: L
authors.lastname: Herlitz
authors.forename: Maria
authors.initials: M
authors.lastname: Abadi
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Michaelson
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D000074049:Cytokine TWEAK; D004195:Disease Models, Animal; D005355:Fibrosis; D015870:Gene Expression; D050533:Glomerular Basement Membrane / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D007106:Immune Sera; D007668:Kidney / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology / Q000473:pathology / Q000628:therapy; D050527:Mesangial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011817:Rabbits; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D000074050:TWEAK Receptor; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; D015415:Biomarkers; D000074049:Cytokine TWEAK; D007106:Immune Sera; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; C491645:Tnfsf12 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors