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TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease

Gomez, I. G., Roach, A. M., Nakagawa, N., Amatucci, A., Johnson, B. G., Dunn, K., Kelly, M.C., Karaca, G., Zheng, T. S., Szak, S., and others. (2016) TWEAK-Fn14 Signaling Activates Myofibroblasts to Drive Progression of Fibrotic Kidney Disease. Journal of the American Society of Nephrology, 27 (12). pp. 3639-3652. ISSN 1046-6673. (doi:10.1681/ASN.2015111227) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:59462)

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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.

Item Type: Article
DOI/Identification number: 10.1681/ASN.2015111227
Uncontrolled keywords: Alport nephropathy; chronic; kidney disease; myofibroblast; pericyte; vascular biology
Subjects: Q Science > QP Physiology (Living systems)
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Claire Peppiatt-Wildman
Date Deposited: 06 Dec 2016 11:58 UTC
Last Modified: 17 Aug 2022 12:21 UTC
Resource URI: (The current URI for this page, for reference purposes)

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Peppiatt-Wildman, Claire M..

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