Irradiation of the kidneys causes pathologic remodeling in the nontargeted heart: A role for the immune system

Lenarczyk, Marek; Laiakis, Evagelia C.; Mattson, David L.; Johnson, Bryon D.; Kronenberg, Amy; North, Paula E.; Komorowski, Richard; Mäder, Marylou; Baker, John E.

doi:10.1096/fba.2020-00071

Title: Irradiation of the kidneys causes pathologic remodeling in the nontargeted heart: A role for the immune system

Journal Article · Fri Oct 23 00:00:00 EDT 2020 · Geography and Sustainability

DOI:https://doi.org/10.1096/fba.2020-00071· OSTI ID:1826902

Lenarczyk, Marek ^[1]; Laiakis, Evagelia C. ^[2]; Mattson, David L. ^[3]; Johnson, Bryon D. ^[1]; Kronenberg, Amy ^[4]; North, Paula E. ^[1]; Komorowski, Richard ^[1]; Mäder, Marylou ^[1];

^[1]

Medical College of Wisconsin, Milwaukee, WI (United States)
Georgetown Univ., Washington, DC (United States)
Medical College of Georgia, Augusta, GA (United States)
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

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.

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Research Organization:: Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Aeronautical and Space Administration (NASA); Greater Milwaukee Foundation

Grant/Contract Number:: AC02-05CH11231; HL116264; HL137748; NNX15AD69G; 80NSSC19K0498

OSTI ID:: 1826902

Journal Information:: Geography and Sustainability, Vol. 2, Issue 12; ISSN 2573-9832

Publisher:: Elsevier; Beijing Normal UniversityCopyright Statement

Country of Publication:: United States

Language:: English

References (52)

Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort Mulrooney, D. A.; Yeazel, M. W.; Kawashima, T. BMJ, Vol. 339, Issue dec08 1 https://doi.org/10.1136/bmj.b4606	journal	December 2009
MetaboAnalyst 3.0—making metabolomics more meaningful Xia, Jianguo; Sinelnikov, Igor V.; Han, Beomsoo Nucleic Acids Research, Vol. 43, Issue W1 https://doi.org/10.1093/nar/gkv380	journal	April 2015
Liver irradiation causes distal bystander effects in the rat brain and affects animal behaviour Kovalchuk, Anna; Mychasiuk, Richelle; Muhammad, Arif Oncotarget, Vol. 7, Issue 4 https://doi.org/10.18632/oncotarget.6596	journal	December 2015
Age at Exposure to Radiation Determines Severity of Renal and Cardiac Disease in Rats Lenarczyk, Marek; Kronenberg, Amy; Mäder, Marylou Radiation Research, Vol. 192, Issue 1 https://doi.org/10.1667/RR15043.1	journal	May 2019
Evidence for Two Patterns of Inheritance of Sensitivity to Induction of Lung Fibrosis in Mice by Radiation, One of Which Involves Two Genes Franko, Allan J.; Sharplin, Janet; Ward, William F. Radiation Research, Vol. 146, Issue 1 https://doi.org/10.2307/3579397	journal	July 1996
In Vivo Space Radiation-Induced Non-Targeted Responses: Late Effects on Molecular Signaling in Mitochondria R. Jain, Mohit; Li, Min; Chen, Wei Current Molecular Pharmacology, Vol. 4, Issue 2 https://doi.org/10.2174/1874467211104020106	journal	June 2011
Treatment-related differences in cardiovascular risk factors in long-term survivors of testicular cancer Wethal, T.; Kjekshus, J.; Røislien, J. Journal of Cancer Survivorship: Research and Practice, Vol. 1, Issue 1 https://doi.org/10.1007/s11764-007-0012-3	journal	March 2007
The Association Between Chronic Kidney Disease and Cardiovascular Disease Risk Factors in Atomic Bomb Survivors Sera, Nobuko; Hida, Ayumi; Imaizumi, Misa Radiation Research, Vol. 179, Issue 1 https://doi.org/10.1667/RR2863.1	journal	January 2013
Lung T Lymphocyte Trafficking and Activation during Ischemic Acute Kidney Injury Lie, Mihaela L.; White, Laura E.; Santora, Rachel J. The Journal of Immunology, Vol. 189, Issue 6 https://doi.org/10.4049/jimmunol.1103254	journal	August 2012
MetaboLyzer: A Novel Statistical Workflow for Analyzing Postprocessed LC–MS Metabolomics Data Mak, Tytus D.; Laiakis, Evagelia C.; Goudarzi, Maryam Analytical Chemistry, Vol. 86, Issue 1 https://doi.org/10.1021/ac402477z	journal	November 2013
CD247 Modulates Blood Pressure by Altering T-Lymphocyte Infiltration in the Kidney Rudemiller, Nathan; Lund, Hayley; Jacob, Howard J. Hypertension, Vol. 63, Issue 3 https://doi.org/10.1161/HYPERTENSIONAHA.113.02191	journal	March 2014
Bile Acids Regulate Cardiovascular Function Khurana, Sandeep; Raufman, Jean-Pierre; Pallone, Thomas L. Clinical and Translational Science, Vol. 4, Issue 3 https://doi.org/10.1111/j.1752-8062.2011.00272.x	journal	June 2011
Cardio-renal interaction: impact of renal function and anemia on the outcome of chronic heart failure Kimura, Hisashi; Hiramitsu, Shinya; Miyagishima, Kenji Heart and Vessels, Vol. 25, Issue 4 https://doi.org/10.1007/s00380-009-1201-y	journal	July 2010
Links between Innate Immunity and Normal Tissue Radiobiology Schaue, Dörthe; McBride, William H. Radiation Research, Vol. 173, Issue 4 https://doi.org/10.1667/RR1931.1	journal	April 2010
Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated Demaria, Sandra; Ng, Bruce; Devitt, Mary Louise International Journal of Radiation OncologyBiologyPhysics, Vol. 58, Issue 3 https://doi.org/10.1016/j.ijrobp.2003.09.012	journal	March 2004
Lipoxygenase contributes to the oxidation of lipids in human atherosclerotic plaques. Folcik, V. A.; Nivar-Aristy, R. A.; Krajewski, L. P. Journal of Clinical Investigation, Vol. 96, Issue 1 https://doi.org/10.1172/JCI118062	journal	July 1995
Trends in Radiation Therapy among Cancer Survivors in the United States, 2000–2030 Bryant, Alex K.; Banegas, Matthew P.; Martinez, Maria Elena Cancer Epidemiology Biomarkers & Prevention, Vol. 26, Issue 6 https://doi.org/10.1158/1055-9965.EPI-16-1023	journal	January 2017
Effect of high-dose total body irradiation on ACTH, corticosterone, and catecholamines in the rat Cohen, Eric P.; Bruder, Eric D.; Cullinan, William E. Translational Research, Vol. 157, Issue 1 https://doi.org/10.1016/j.trsl.2010.09.007	journal	January 2011
Late Effects in Mouse Heart after ⁶⁰ Co γ-irradiation of the Brain: An Ultrastructural Study Yang, V. C.; Kao, C. -H.; Ting, W. -H. International Journal of Radiation Biology, Vol. 57, Issue 6 https://doi.org/10.1080/09553009014551311	journal	January 1990
The Swedish Council on Technology Assessment in Health Care (SBU) Systematic Overview of Radiotherapy for Cancer including a Prospective Survey of Radiotherapy Practice in Sweden 2001--Summary and Conclusions Ringborg, Ulrik; Bergqvist, David; Brorsson, Bengt Acta Oncologica, Vol. 42, Issue 5-6 https://doi.org/10.1080/02841860310010826	journal	January 2003
Impact of Angiotensin II Type 2 Receptor Blockade on Experimental Radiation Nephropathy Moulder, John E.; Fish, Brian L.; Cohen, Eric P. Radiation Research, Vol. 161, Issue 3 https://doi.org/10.1667/RR3129	journal	March 2004
Abscopal effect of low-LET γ-radiation mediated through Rel protein signal transduction in a mouse model of nontargeted radiation response Aravindan, S.; Natarajan, M.; Ramraj, S. K. Cancer Gene Therapy, Vol. 21, Issue 2 https://doi.org/10.1038/cgt.2013.72	journal	December 2013
Cardiorenal Syndrome: Classification, Pathophysiology, Diagnosis, and Treatment Strategies: A Scientific Statement From the American Heart Association Rangaswami, Janani; Bhalla, Vivek; Blair, John E. A. Circulation, Vol. 139, Issue 16 https://doi.org/10.1161/CIR.0000000000000664	journal	April 2019
Effects of radiation on normal tissue: consequences and mechanisms Stone, Helen B.; Coleman, C. Norman; Anscher, Mitchell S. The Lancet Oncology, Vol. 4, Issue 9 https://doi.org/10.1016/S1470-2045(03)01191-4	journal	September 2003
Kidney Disease as a Risk Factor for Development of Cardiovascular Disease: A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention Sarnak, Mark J.; Levey, Andrew S.; Schoolwerth, Anton C. Circulation, Vol. 108, Issue 17 https://doi.org/10.1161/01.CIR.0000095676.90936.80	journal	October 2003
Late Structural Changes in Mouse Coronary Arteries after Iron-Particle Irradiation of the Orbital Region Yang, Vivian C. Radiation Research, Vol. 134, Issue 3 https://doi.org/10.2307/3578202	journal	June 1993
Inflammatory-type responses after exposure to ionizing radiation in vivo: a mechanism for radiation-induced bystander effects? Lorimore, Sally A.; Coates, Philip J.; Scobie, Gillian E. Oncogene, Vol. 20, Issue 48 https://doi.org/10.1038/sj.onc.1204903	journal	October 2001
Increased Perfusion Pressure Drives Renal T-Cell Infiltration in the Dahl Salt-Sensitive Rat Evans, Louise C.; Petrova, Galina; Kurth, Theresa Hypertension, Vol. 70, Issue 3 https://doi.org/10.1161/HYPERTENSIONAHA.117.09208	journal	September 2017
Rodent Immunohistochemistry: Pitfalls and Troubleshooting Ward, J. M.; Rehg, J. E. Veterinary Pathology, Vol. 51, Issue 1 https://doi.org/10.1177/0300985813503571	journal	September 2013
Cardiovascular Disease as a Long-Term Complication of Treatment for Testicular Cancer Huddart, R. A.; Norman, A.; Shahidi, M. Journal of Clinical Oncology, Vol. 21, Issue 8 https://doi.org/10.1200/JCO.2003.04.173	journal	April 2003
Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart Desai, Moreshwar S.; Mathur, Bhoomika; Eblimit, Zeena Hepatology, Vol. 65, Issue 1 https://doi.org/10.1002/hep.28890	journal	November 2016
Mitigation of Radiation Injuries via Suppression of the Renin-Angiotensin System: Emphasis on Radiation Nephropathy P. Cohen, E.; L. Fish, B.; E. Moulder, J. Current Drug Targets, Vol. 11, Issue 11 https://doi.org/10.2174/1389450111009011423	journal	November 2010
Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular disease Porez, Geoffrey; Prawitt, Janne; Gross, Barbara Journal of Lipid Research, Vol. 53, Issue 9 https://doi.org/10.1194/jlr.R024794	journal	September 2012
Cardiovascular Status in Long-Term Survivors of Hodgkin's Disease Treated With Chest Radiotherapy Adams, M. Jacob; Lipsitz, Stuart R.; Colan, Steven D. Journal of Clinical Oncology, Vol. 22, Issue 15 https://doi.org/10.1200/JCO.2004.09.109	journal	August 2004
Whole Body Irradiation—Radiobiology or Medicine? Mole, R. H. The British Journal of Radiology, Vol. 26, Issue 305 https://doi.org/10.1259/0007-1285-26-305-234	journal	May 1953
Usefulness of serum interleukin-18 in predicting cardiovascular mortality in patients with chronic kidney disease – systems and clinical approach Formanowicz, Dorota; Wanic-Kossowska, Maria; Pawliczak, Elżbieta Scientific Reports, Vol. 5, Issue 1 https://doi.org/10.1038/srep18332	journal	December 2015
A perpetual cascade of cytokines postirradiation leads to pulmonary fibrosis Rubin, Philip; Johnston, Carl J.; Williams, Jacqueline P. International Journal of Radiation OncologyBiologyPhysics, Vol. 33, Issue 1 https://doi.org/10.1016/0360-3016(95)00095-G	journal	August 1995
Renal dysfunction after total body irradiation: Dose-effect relationship: In regard to Kal and van Kempen-Harteveld (Int J Radiat Oncol Biol Phys 2006;65:1228–1232) Moulder, John E.; Cohen, Eric P. International Journal of Radiation OncologyBiologyPhysics, Vol. 67, Issue 1 https://doi.org/10.1016/j.ijrobp.2006.09.006	journal	January 2007
Radiation Dose Associated with Renal Failure Mortality: A Potential Pathway to Partially Explain Increased Cardiovascular Disease Mortality Observed after Whole-Body Irradiation Adams, Michael Jacob; Grant, Eric J.; Kodama, Kazunori Radiation Research, Vol. 177, Issue 2 https://doi.org/10.1667/RR2746.1	journal	December 2011
Metabolic Dysregulation after Neutron Exposures Expected from an Improvised Nuclear Device Laiakis, Evagelia C.; Wang, Yi-Wen; Young, Erik F. Radiation Research, Vol. 188, Issue 1 https://doi.org/10.1667/RR14656.1	journal	May 2017
Modifying Normal Tissue Damage Postirradiation: Report of a Workshop Sponsored by the Radiation Research Program, National Cancer Institute, Bethesda, Maryland September 6–8, 2000 Stone, Helen B.; McBride, William H.; Coleman, C. Norman Radiation Research, Vol. 157, Issue 2 https://doi.org/10.1667/0033-7587(2002)157[0204:MNTDP]2.0.CO;2	journal	February 2002
Comparison of three rat strains for development of radiation-induced lung injury after hemithoracic irradiation van Eerde, Mark R.; Kampinga, Harm H.; Szabo, Ben G. Radiotherapy and Oncology, Vol. 58, Issue 3, p. 313-316 https://doi.org/10.1016/S0167-8140(00)00301-7	journal	March 2001
Kidney-Sparing Methods for Extended-Field Intensity-Modulated Radiotherapy (EF-IMRT) in Cervical Carcinoma Treatment Kunogi, Hiroaki; Yamaguchi, Nanae; Terao, Yasuhisa PLOS ONE, Vol. 11, Issue 6 https://doi.org/10.1371/journal.pone.0156623	journal	June 2016
Distinct serum metabolomics profiles associated with malignant progression in the KrasG12Dmouse model of pancreatic ductal adenocarcinoma LaConti, Joseph J.; Laiakis, Evagelia C.; Mays, Anne Deslattes BMC Genomics, Vol. 16, Issue S1 https://doi.org/10.1186/1471-2164-16-S1-S1	journal	January 2015
Effect of chronic renal failure on the hepatic, intestinal, and renal expression of bile acid transporters Gai, Zhibo; Chu, Lei; Hiller, Christian American Journal of Physiology-Renal Physiology, Vol. 306, Issue 1 https://doi.org/10.1152/ajprenal.00114.2013	journal	January 2014
Glutamine Oxidation Maintains the TCA Cycle and Cell Survival during Impaired Mitochondrial Pyruvate Transport Yang, Chendong; Ko, Bookyung; Hensley, Christopher T. Molecular Cell, Vol. 56, Issue 3 https://doi.org/10.1016/j.molcel.2014.09.025	journal	November 2014
Effects of Radiation on Blood Pressure and Body Weight in the Spontaneously Hypertensive Rat Model. Are Radiation Effects on Blood Pressure Affected by Genetic Background? Takahashi, Norio; Misumi, Munechika; Niwa, Yasuharu Radiation Research, Vol. 193, Issue 6 https://doi.org/10.1667/RR15536.1	journal	March 2020
A Sense of Danger from Radiation ¹ McBride, William H.; Chiang, Chi-Shiun; Olson, Jennifer L. Radiation Research, Vol. 162, Issue 1 https://doi.org/10.1667/RR3196	journal	July 2004
An analysis of variance test for normality (complete samples) Shapiro, S. S.; Wilk, M. B. Biometrika, Vol. 52, Issue 3-4 https://doi.org/10.1093/biomet/52.3-4.591	journal	December 1965
Delayed molecular responses to brain irradiation Chiang, J. -H. Hong, A. Stalder, J. -, C. -S. International Journal of Radiation Biology, Vol. 72, Issue 1 https://doi.org/10.1080/095530097143527	journal	January 1997
In vivo action of 15-lipoxygenase in early stages of human atherogenesis. Kühn, H.; Heydeck, D.; Hugou, I. Journal of Clinical Investigation, Vol. 99, Issue 5 https://doi.org/10.1172/JCI119253	journal	March 1997
Involvement of 15-lipoxygenase in early stages of atherogenesis. Kühn, H.; Belkner, J.; Zaiss, S. Journal of Experimental Medicine, Vol. 179, Issue 6 https://doi.org/10.1084/jem.179.6.1903	journal	June 1994

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Title: Irradiation of the kidneys causes pathologic remodeling in the nontargeted heart: A role for the immune system

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