Rictor/mammalian target of rapamycin complex 2 promotes macrophage activation and kidney fibrosis.
Jiafa RenJianzhong LiYe FengBingyan ShuYuan GuiWei WeiWeichun HeJunwei YangChunsun DaiPublished in: The Journal of pathology (2017)
Mammalian target of rapamycin (mTOR) signalling controls many essential cellular functions. However, the role of Rictor/mTOR complex 2 (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 reduced kidney fibrosis, inflammatory cell accumulation, macrophage proliferation and polarization after unilateral ureter obstruction or ischaemia/reperfusion injury. In bone marrow-derived macrophages (BMMs), deletion of Rictor or blockade of protein kinase Cα inhibited cell migration. Additionally, deletion of Rictor or blockade of Akt abolished interleukin-4-stimulated or transforming growth factor (TGF)-β1-stimulated macrophage M2 polarization. Furthermore, deletion of Rictor downregulated TGF-β1-stimulated upregulation of multiple profibrotic cytokines, including platelet-derived growth factor, vascular endothelial growth factor and connective tissue growth factor, in BMMs. Conditioned medium from TGF-β1-pretreated Rictor-/- macrophages stimulated fibroblast activation less efficiently than that from TGF-β1-pretreated Rictor+/+ macrophages. These results demonstrate that Rictor/mTORC2 signalling can promote macrophage activation and kidney fibrosis. Targeting this signalling pathway in macrophages may shine light on ways to protect against kidney fibrosis in patients with chronic kidney diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Keyphrases
- transforming growth factor
- growth factor
- adipose tissue
- epithelial mesenchymal transition
- vascular endothelial growth factor
- cell proliferation
- cell migration
- signaling pathway
- liver fibrosis
- acute myocardial infarction
- heart failure
- insulin resistance
- single cell
- brain injury
- endothelial cells
- acute coronary syndrome
- cell therapy
- poor prognosis
- skeletal muscle
- cerebral ischemia
- cancer therapy