@article{7cf8cfd5884d4c38ba6287e1c27ff1d5,
title = "Irradiation of the kidneys causes pathologic remodeling in the nontargeted heart: A role for the immune system",
abstract = "Cardiac disease is a frequent and significant adverse event associated with radiotherapy for cancer. Identifying the underlying mechanism responsible for radiation injury to the heart will allow interventions to be developed. In the present study, we tested if local kidney irradiation results in remodeling of the shielded, nontargeted heart. One kidney, two kidneys, or the total body of male WAG and Dahl SS rats were irradiated with 10 Gy of X-rays. Local kidney irradiation resulted in systemic hypertension, increased BUN, infiltration of T lymphocytes, natural killer cells, and macrophages into the renal cortex and medulla, and renal fibrosis. Local irradiation of kidneys in WAG rats resulted in remodeling in the nontargeted heart after 120 days, manifested by perivascular fibrosis and increased interventricular septal thickness, but was not seen in Dahl SS rats due to a high baseline level of fibrosis in the sham-irradiated animals. Genetic depletion of T cells mitigated the nephropathy after local kidney irradiation, indicating a role for the immune system in mediating this outcome. Local kidney irradiation resulted in a cascade of pro-inflammatory cytokines and low-molecular weight metabolites into the circulation associated with transmission of signals resulting in pathologic remodeling in the nontargeted heart. A new model is proposed whereby radiation-induced cardiac remodeling in susceptible animals is indirect, with lower hemi body organs such as the kidney exporting factors into the circulation that cause remodeling outside of the irradiated field in the shielded, nontargeted heart. This nontargeted effect appears to be mediated, in part, by the immune system.",
keywords = "Fibrosis, T lymphocytes, X-rays, cytokines, heart diseases, hypertension, rats",
author = "Marek Lenarczyk and Laiakis, {Evagelia C.} and Mattson, {David L.} and Johnson, {Bryon D.} and Amy Kronenberg and North, {Paula E.} and Richard Komorowski and Marylou M{\"a}der and Baker, {John E.}",
note = "Funding Information: We gratefully acknowledge Maggy Schultz (deceased) for inspiration and fundraising, Natalya Morrow for dosimetry, Qunli Chen for blood pressure measurements, Brian Fish, Tracy Gasperetti, and Dana Scholler for irradiations, Galina Petrova for flow cytometry, Christine Duris for histology core services, Suresh Kumar for image quantification, and Leanne Harmann for echocardiography. Supported by grants from the National Institutes of Health (HL116264, HL137748), National Aeronautical and Space Administration (NNX15AD69G, 80NSSC19K0498), the Greater Milwaukee Foundation, the We Care Fund and the Foundation for Heart Science. The project was also supported by Award Number P30 CA051008 (P.I. Louis Weiner) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. Funding Information: We gratefully acknowledge Maggy Schultz (deceased) for inspiration and fundraising, Natalya Morrow for dosimetry, Qunli Chen for blood pressure measurements, Brian Fish, Tracy Gasperetti, and Dana Scholler for irradiations, Galina Petrova for flow cytometry, Christine Duris for histology core services, Suresh Kumar for image quantification, and Leanne Harmann for echocardiography. Supported by grants from the National Institutes of Health (HL116264, HL137748), National Aeronautical and Space Administration (NNX15AD69G, 80NSSC19K0498), the Greater Milwaukee Foundation, the We Care Fund and the Foundation for Heart Science. The project was also supported by Award Number P30 CA051008 (P.I. Louis Weiner) from the National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. Publisher Copyright: {\textcopyright}2020 The Authors. FASEB BioAdvances published by The Federation of American Societies for Experimental Biology",
year = "2020",
month = dec,
doi = "10.1096/fba.2020-00071",
language = "English (US)",
volume = "2",
pages = "705--719",
journal = "FASEB BioAdvances",
issn = "2573-9832",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "12",
}