دورية أكاديمية
Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis.
| العنوان: | Indian Hedgehog release from TNF-activated renal epithelia drives local and remote organ fibrosis. |
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| المؤلفون: | O'Sullivan ED; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.; Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia., Mylonas KJ; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Xin C; Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Baird DP; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Carvalho C; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Docherty MH; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Campbell R; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Matchett KP; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Waddell SH; Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK., Walker AD; Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK., Gallagher KM; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.; Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK., Jia S; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Leung S; Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK., Laird A; Department of Urology, Western General Hospital, Edinburgh EH4 2XU, UK., Wilflingseder J; Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.; Department of Physiology and Pathophysiology, University of Veterinary Medicine, Veterinärplatz 1, 1210 Vienna, Austria., Willi M; Laboratory of Genetics and Physiology, NIDDK, NIH, Bethesda, MD 20892, USA., Reck M; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Finnie S; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Pisco A; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA., Gordon-Keylock S; Centre for Regenerative Medicine. University of Edinburgh, Edinburgh EH16 4UU, UK., Medvinsky A; Centre for Regenerative Medicine. University of Edinburgh, Edinburgh EH16 4UU, UK., Boulter L; Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK., Henderson NC; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.; Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK., Kirschner K; School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK., Chandra T; Cancer Research UK Scotland Centre and MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK., Conway BR; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Hughes J; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Denby L; Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK., Bonventre JV; Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA., Ferenbach DA; Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.; Renal Division and Division of Engineering in Medicine, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. |
| المصدر: | Science translational medicine [Sci Transl Med] 2023 May 31; Vol. 15 (698), pp. eabn0736. Date of Electronic Publication: 2023 May 31. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101505086 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1946-6242 (Electronic) Linking ISSN: 19466234 NLM ISO Abbreviation: Sci Transl Med Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : American Association for the Advancement of Science |
| مواضيع طبية MeSH: | Hedgehog Proteins*/metabolism , Renal Insufficiency, Chronic*, Animals ; Humans ; Mice ; Fibrosis ; Inflammation ; NF-kappa B ; Tumor Necrosis Factors ; Zinc Finger Protein GLI1 |
| مستخلص: | 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. |
| التعليقات: | Comment in: Nat Rev Nephrol. 2023 Aug;19(8):478. doi: 10.1038/s41581-023-00735-8. (PMID: 37386290) |
| معلومات مُعتمدة: | United Kingdom WT_ Wellcome Trust; MR/N002210/1 United Kingdom MRC_ Medical Research Council; United Kingdom BHF_ British Heart Foundation; R37 DK039773 United States DK NIDDK NIH HHS; R01 DK072381 United States DK NIDDK NIH HHS; MR/W000148/1 United Kingdom MRC_ Medical Research Council; UG3 TR002155 United States TR NCATS NIH HHS; MR/W00089X/1 United Kingdom MRC_ Medical Research Council |
| المشرفين على المادة: | 0 (Hedgehog Proteins) 0 (NF-kappa B) 0 (Tumor Necrosis Factors) 0 (Zinc Finger Protein GLI1) 0 (IHH protein, human) 0 (ihh protein, mouse) |
| تواريخ الأحداث: | Date Created: 20230531 Date Completed: 20231020 Latest Revision: 20240615 |
| رمز التحديث: | 20240615 |
| DOI: | 10.1126/scitranslmed.abn0736 |
| PMID: | 37256934 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1946-6242 |
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| DOI: | 10.1126/scitranslmed.abn0736 |