Sympathetic nerve promotes renal fibrosis by activating M2 macrophages through β2-AR-Gsa

Abstract

Sympathetic nervous system overactivation is directly related to renal fibrosis. This study focused on the role of and mechanism by which sympathetic signaling regulates macrophage activation, as well as the contribution to renal fibrosis. Renal denervation alleviated tubular necrosis, tubulointerstitial fibrosis, and macrophage accumulation induced by unilateral ureteral obstruction and ischemia-reperfusion injury. In vitro, norepinephrine (NE) promoted macrophage alternative (M2) polarization by activating β2-adrenergic receptor (β2-AR) and heterotrimeric G stimulatory protein α-subunit (Gsa). The effects of NE-induced macrophage M2 polarization were blocked by a β2-AR selective antagonist and Gsa siRNA. Importantly, ablation of Gsa in macrophages alleviated tubulointerstitial fibrosis, macrophage accumulation, and M2 polarization in the renal ischemia-reperfusion injury model. Sympathetic nervous system overactivation regulates M2 polarization in macrophages as an important neuroimmune mechanism of renal fibrosis. The β2-AR-Gsa signaling pathway was responsible for NE-induced macrophage M2 polarization, which may be a therapeutic target for renal fibrosis.

Keywords: Gsa; Macrophage; Norepinephrine; Renal fibrosis; Sympathetic nerve.