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 Ly6C 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 Ly6C 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.

Proximal Tubule β2-Adrenergic Receptor Mediates Formoterol-Induced Recovery of Mitochondrial and Renal Function after Ischemia-Reperfusion Injury

“…Other groups have shown that wholebody deletion of the b 1 AR and b 2 AR reduces baseline renin levels but has a normal response to stimulation (Chen et al, 2010;Neubauer et al, 2011). Additionally, deletion of b 2 AR decreases the activity of a collecting duct-macrophage axis after transverse aortic constriction, although renal function was not measured in these experiments (Fujiu et al, 2017). These effects on renal signaling likely are effects of b 2 AR inhibition on cell types other than the proximal tubule cell.…”

Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy

“…The upstream mechanism following POH that leads to KLF4 induction remains incompletely understood. However, a recent study by Fujiu et al (33) reported that kidney-derived CSF2 activated proliferation of cardiac resident macrophages in response to TAC. We observed that myeloid KLF4 deficiency significantly diminished macrophage proliferation in response to CSF2 (as well as CSF1; Fig.…”

Gene expression signatures identify pediatric patients with multiple organ dysfunction who require advanced life support in the intensive care unit

“…We found the gene AREG which regulates Amphiregulin a mediator for macrophage activity were preferentially activated in patients prior to ECMO [18][19]. Amphiregulin has been shown to an essential cardioprotective mediator produced by cardiac Ly6C macrophages in response to fluid overload, which is not unusual in MODS [20].…”