TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease
| Autor: | Naoki Nakagawa, Kadeshia Dunn, Mark C. Kelly, Claire M. Peppiatt-Wildman, Aldo Amatucci, Jeremy S. Duffield, Linda C. Burkly, Suzanne Szak, Timothy S. Zheng, Bryce G. Johnson, Ivan G. Gomez, Gamze Karaca, Allie M. Roach |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
030232 urology & nephrology Inflammation Kidney Receptors Tumor Necrosis Factor Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Genetic model Animals Medicine Myofibroblasts Cytokine TWEAK Innate immune system business.industry General Medicine QP Fibrosis Basic Research 030104 developmental biology medicine.anatomical_structure TWEAK Receptor Nephrology Tumor Necrosis Factors Immunology Disease Progression Cancer research Kidney Diseases Pericyte medicine.symptom Signal transduction business Myofibroblast Signal Transduction |
| Zdroj: | Journal of the American Society of Nephrology. 27:3639-3652 |
| ISSN: | 1533-3450 1046-6673 |
| DOI: | 10.1681/asn.2015111227 |
| Popis: | The identification of the cellular origins of myofibroblasts has led to the discovery of novel pathways that potentially drive myofibroblast perpetuation in disease. Here, we further investigated the role of innate immune signaling pathways in this process. In mice, renal injury-induced activation of pericytes, which are myofibroblast precursors attached to endothelial cells, led to upregulated expression of TNF receptor superfamily member 12a, also known as fibroblast growth factor-inducible 14 (Fn14), by these cells. In live rat kidney slices, administration of the Fn14 ligand, TNF-related weak inducer of apoptosis (TWEAK), promoted pericyte-dependent vasoconstriction followed by pericyte detachment from capillaries. In vitro, administration of TWEAK activated and differentiated pericytes into cytokine-producing myofibroblasts, and further activated established myofibroblasts in a manner requiring canonical and noncanonical NF-?B signaling pathways. Deficiency of Fn14 protected mouse kidneys from fibrogenesis, inflammation, and associated vascular instability after in vivo injury, and was associated with loss of NF-?B signaling. In a genetic model of spontaneous CKD, therapeutic delivery of anti-TWEAK blocking antibodies attenuated disease progression, preserved organ function, and increased survival. These results identify the TWEAK-Fn14 signaling pathway as an important factor in myofibroblast perpetuation, fibrogenesis, and chronic disease progression. |
| Databáze: | OpenAIRE |
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