Indian Hedgehog release from TNF activated renal epithelia drives local and remote organ fibrosis

O’Sullivan, E. D. et al. (2023) Indian Hedgehog release from TNF activated renal epithelia drives local and remote organ fibrosis. Science Translational Medicine, 15(698), eabn07. (doi: 10.1126/scitranslmed.abn0736) (PMID:37256934)

Abstract

Progressive fibrosis is a feature of aging and chronic tissue injury in multiple organs, including the kidney and heart. Glioma-associated oncogene 1 expressing (Gli1+) cells are a major source of activated fibroblasts in multiple organs, but the links between injury, inflammation, and Gli1+ cell expansion and tissue fibrosis remain incompletely understood. We demonstrated that leukocyte-derived tumor necrosis factor (TNF) promoted Gli1+ cell proliferation and cardiorenal fibrosis through induction and release of Indian Hedgehog (IHH) from renal epithelial cells. Using single-cell–resolution transcriptomic analysis, we identified an “inflammatory” proximal tubular epithelial (iPT) population contributing to TNF- and nuclear factor κB (NF-κB)–induced IHH production in vivo. TNF-induced Ubiquitin D (Ubd) expression was observed in human proximal tubular cells in vitro and during murine and human renal disease and aging. Studies using pharmacological and conditional genetic ablation of TNF-induced IHH signaling revealed that IHH activated canonical Hedgehog signaling in Gli1+ cells, which led to their activation, proliferation, and fibrosis within the injured and aging kidney and heart. These changes were inhibited in mice by Ihh deletion in Pax8-expressing cells or by pharmacological blockade of TNF, NF-κB, or Gli1 signaling. Increased amounts of circulating IHH were associated with loss of renal function and higher rates of cardiovascular disease in patients with chronic kidney disease. Thus, IHH connects leukocyte activation to Gli1+ cell expansion and represents a potential target for therapies to inhibit inflammation-induced fibrosis.

• Item Type: Articles
• Additional Information: EOS was supported by a Clinical Training fellowship from Kidney Research UK [TF_006_20161125]. KJM is supported by a Senior Fellowship from Kidney Research UK Fellowship [CSO_PDF/2018/1]. DB and MD are supported by MRC Clinical Training Fellowships. KG was funded by the Chief Scientist Office Scotland [CSO TCS/18/15], Kidney Research UK and the MRC. AL is supported by the Chief Scientist Office Scotland with a NRS Career Researcher Fellowship. JW is supported by the Austrian Science Fund (P30373). BRC was supported by a Kidney Research UK project grant [RP30/2015]. LD is supported by a Senior Fellowship from Kidney Research UK [SF_001_20181122] and funding from British Heart Foundation Ph.D. studentship FS/15/63/32033. AM is supported by the MRC. KK is supported by the MRC (MR/W000148/1). LB is supported by Cancer Research UK (C52499/A27948). NCH is supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (ref. 219542/Z/19/Z). RC is supported by the Wellcome Trust (108906/Z/15/Z). JVB is supported by grants from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (UH3 TR002155 and R37 DK39773, and RO1 DK072381). DAF was supported by an Intermediate Clinical Fellowship from the Wellcome Trust [100171/Z/12/Z] and a Senior Clinical Fellowship from the MRC [MR/X006735/1].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kirschner, Dr Kristina
• Authors: O’Sullivan, E. D., Mylonas, K. J., Xin, C., Baird, D., Carvalho, C., Docherty, M.-H., Campbell, R., Matchett, K. P., Waddell, S. H., Walker, A., Gallagher, K. M., Jia, S., Leung, S., Laird, A., Wilflingseder, J., Willi, M., Reck, M., Finnie, S., Pisco, A., Gordon-Keylock, S., Medvinsky, A., Boulter, L., Henderson, N. C., Kirschner, K., Chandra, T., Conway, B. R., Hughes, J., Denby, L., Bonventre, J. V., and Ferenbach, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Science Translational Medicine
• Publisher: American Association for the Advancement of Science
• ISSN: 1946-6234
• ISSN (Online): 1946-6242
• Published Online: 31 May 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Science Translational Medicine 15(698):eabn07
• Publisher Policy: Reproduced in accordance with the publisher copyright policy