Rictor/mTORC2 promotes macrophage activation and kidney fibrosis

ABSTRACT

Mammalian target of rapamycin (mTOR) signaling controls many essential cellular functions. However, the role for Rictor/mTORC2 in regulating macrophage activation and kidney fibrosis remains largely unknown. We report here that Rictor/mTORC2 was activated in macrophages from the fibrotic kidneys of mice. Ablation of Rictor in macrophages diminished kidney fibrosis, inflammatory cell accumulation, macrophage proliferation and polarization after unilateral ureter obstruction (UUO) or ischemia/reperfusion injury (IRI). In macrophages derived from bone marrow (BMMs), deletion of Rictor or blockade of PKCα inhibited cell migration. Additionally, deletion of Rictor or blockade of Akt abolished IL4- or TGFβ1-stimulated macrophage M2 polarization. Furthermore, deletion of Rictor could down regulate TGFβ1-stimulated up-regulation of multiple profibrotic cytokines including PDGF, VEGF and CTGF in BMMs. Conditioned media from TGFβ1-pretreated Rictor−/− macrophages could less efficiently stimulate fibroblast activation compared to those from TGFβ1-pretreated Rictor+/+ macrophages. These results demonstrate that Rictor/mTORC2 signaling can promote macrophage activation and kidney fibrosis. Targeting this signaling pathway in macrophages may shine light on ways to protect against kidney fibrosis in patients with chronic kidney diseases.

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