title: A heart-brain-kidney network controls adaptation to cardiac stress through tissue macrophage activation.
abstract: Heart failure is a complex clinical syndrome characterized by insufficient cardiac function. In addition to abnormalities intrinsic to the heart, dysfunction of other organs and dysregulation of systemic factors greatly affect the development and consequences of heart failure. Here we show that the heart and kidneys function cooperatively in generating an adaptive response to cardiac pressure overload. In mice subjected to pressure overload in the heart, sympathetic nerve activation led to activation of renal collecting-duct (CD) epithelial cells. Cell-cell interactions among activated CD cells, tissue macrophages and endothelial cells within the kidney led to secretion of the cytokine CSF2, which in turn stimulated cardiac-resident Ly6Clomacrophages, which are essential for the myocardial adaptive response to pressure overload. The renal response to cardiac pressure overload was disrupted by renal sympathetic denervation, adrenergic β2-receptor blockade or CD-cell-specific deficiency of the transcription factor KLF5. Moreover, we identified amphiregulin as an essential cardioprotective mediator produced by cardiac Ly6Clomacrophages. Our results demonstrate a dynamic interplay between the heart, brain and kidneys that is necessary for adaptation to cardiac stress, and they highlight the homeostatic functions of tissue macrophages and the sympathetic nervous system.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.|Translational Systems Biology and Medicine Initiative, University of Tokyo, Tokyo, Japan.|PRESTO, Japan Science and Technology Agency (JST), Research Division Gobancho Building, Tokyo, Japan.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Fujiu
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Munehiko
authors.initials: M
authors.lastname: Shibata
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yukiteru
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Fusa
authors.initials: F
authors.lastname: Ogata
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Sahohime
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Koji
authors.identifier: http://orcid.org/0000-0002-9510-5897
authors.initials: K
authors.lastname: Noshita
authors.affiliation: PRESTO, Japan Science and Technology Agency (JST), Research Division Gobancho Building, Tokyo, Japan.|Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.|CREST, Japan Science and Technology Agency, Research Division Gobancho Building, Tokyo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Iwami
authors.affiliation: PRESTO, Japan Science and Technology Agency (JST), Research Division Gobancho Building, Tokyo, Japan.|Laboratory of Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Nakae
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.affiliation: Jichi Medical University, Tochigi, Japan.
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.affiliation: Department of Disease Biology and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Manabe
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics / Q000276:immunology*; D000319:Adrenergic beta-Antagonists; D066258:Amphiregulin / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000601:surgery; D001127:Arginine Vasopressin / Q000378:metabolism; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D001921:Brain / Q000502:physiology / Q000503:physiopathology*; D040501:Calgranulin A; D040502:Calgranulin B / Q000494:pharmacology; D004452:Echocardiography; D042783:Endothelial Cells; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D005919:Glomerular Filtration Rate; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D007150:Immunohistochemistry; D007668:Kidney / Q000503:physiopathology*; D007685:Kidney Tubules, Collecting / Q000166:cytology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000276:immunology*; D009638:Norepinephrine / Q000378:metabolism / Q000652:urine; D060888:Real-Time Polymerase Chain Reaction; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D012077:Renal Artery / Q000294:innervation; D013312:Stress, Physiological; D013562:Sympathectomy; D013564:Sympathetic Nervous System / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: C547788:Adrb1 protein, mouse; D000319:Adrenergic beta-Antagonists; D066258:Amphiregulin; C587849:Areg protein, mouse; D040501:Calgranulin A; D040502:Calgranulin B; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D001127:Arginine Vasopressin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D009638:Norepinephrine