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A heart–brain–kidney network controls adaptation to cardiac stress through tissue macrophage activation

Nature Medicine volume 23, pages 611–622 (2017)Cite this article

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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 Ly6Clo macrophages, 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 Ly6Clo macrophages. 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.

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Figure 1: Renal Klf5 deletion disrupts the cardiac adaptive response to pressure overload and affects cardiac macrophage expansion.
Figure 2: Cardiac macrophages are essential for the cardiac adaptive response.
Figure 3: Macrophage-derived AREG mediates the cardiac adaptive response to TAC.
Figure 4: The kidney controls local macrophage proliferation in the heart after TAC.
Figure 5: Sympathetic activation links the heart and kidneys in the adaptive response to TAC.
Figure 6: β2-adrenergic receptor signaling regulates CD cell activation.

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Acknowledgements

We gratefully acknowledge the excellent technical assistance of M. Hayashi, N. Yamanaka, A. Ono, X. Yingda and H. Tomita. Areg-knockout mice were a generous gift from D. Lee (University of Georgia). This study was supported in part by the Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program) from the Japan Society for the Promotion of Science (R.N.), and by grants-in-aid (26461125 (K.F.), 15H01506 (I.M.), 16H05295 (I.M.), 16K15437 ((I.M.))) from the MEXT Japan, a grant for the Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program of MEXT (R.N.), the AMED-CREST from the Japan Agency for Medical Research and Development (AMED) (I.M.), PRESTO from JST (K.F.), grants from the Kanae foundation (K.F.); a Sakakibara Memorial Research Grant from the Japan Research Promotion Society for Cardiovascular Diseases (K.F.), the Banyu Life Science Foundation (K.F.), the Takeda Science Foundation (I.M.), the Mitsubishi Foundation (I.M.), and the SENSHIN Medical Science Foundation (I.M.).

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  1. Katsuhito Fujiu and Munehiko Shibata: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan

    Katsuhito Fujiu, Munehiko Shibata, Yukiteru Nakayama, Fusa Ogata, Sahohime Matsumoto & Issei Komuro

  2. Translational Systems Biology and Medicine Initiative, University of Tokyo, Tokyo, Japan

    Katsuhito Fujiu

  3. Research Division Gobancho Building, PRESTO, Japan Science and Technology Agency (JST), Tokyo, Japan

    Katsuhito Fujiu, Shingo Iwami & Susumu Nakae

  4. Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan

    Koji Noshita

  5. Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan

    Shingo Iwami

  6. Research Division Gobancho Building, CREST, Japan Science and Technology Agency, Tokyo, Japan

    Shingo Iwami

  7. Laboratory of Systems Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

    Susumu Nakae

  8. Jichi Medical University, Tochigi, Japan

    Ryozo Nagai

  9. Department of Disease Biology and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan

    Ichiro Manabe

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Contributions

K.F., I.M. and R.N. conceived and designed the project; K.F., M.S., Y.N., F.O. and S.M. performed the experiments; K.F., M.S. and I.M. analyzed the data and wrote the manuscript; S.N. provided the Areg−/− mice; I.K. contributed to data interpretation; and K.N. and S.I. performed computational analyses.

Corresponding authors

Correspondence to Ryozo Nagai or Ichiro Manabe.

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Supplementary Figures 1–41 and Supplementary Tables 1–3. (PDF 7110 kb)

Supplementary Video 1

CD-Klf5KO mouse 6 weeks after TAC (WMV 3099 kb)

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Fujiu, K., Shibata, M., Nakayama, Y. et al. A heart–brain–kidney network controls adaptation to cardiac stress through tissue macrophage activation. Nat Med 23, 611–622 (2017). https://doi.org/10.1038/nm.4326

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