Figure 1 Heart–brain–kidney interactions control cardiac remodelling Figure 1 | Heart–brain–kidney interactions control cardiac remodelling. In response to stress factors (for example hypoxia), afferent neurons signal to the brain and activate the sympathetic nervous system, which signals to the kidney via renal efferent neurons. This signalling results in the activation of two systems: the renin–angiotensin–aldosterone system and the kidney–heart macrophage axis. β1‑adrenergic (β1‑AR) stimulation induces renin secretion by juxtaglomerular cells, which leads to the production of angiotensin (Ang) II, renal Na+ reabsorption and water retention, and elevated blood pressure. Ang II also directly stimulates pathological cardiomyocyte hypertrophy and fibrosis. β2‑AR stimulation induces expression of the transcription factor KLF5 in collecting duct cells, which leads to production and secretion of S100A8 and S100A9. These proteins activate kidney macrophages, which secrete tumour necrosis factor (TNF). In turn, TNF stimulates kidney endothelial cells to secrete granulocyte–macrophage colony-stimulating factor (GM‑CSF) into the circulation. Circulating GM‑CSF stimulates the proliferation of cardiac M2 macrophages that produce amphiregulin (AREG), which stimulates cardiomyocyte hypertrophy and cardiac fibrosis. Silljé, H. H. W. & de Boer, R. A. (2017) Macrophages take centre stage in the heart–brain–kidney axis Nat. Rev. Nephrol. doi:10.1038/nrneph.2017.73