Rictor/mammalian target of rapamycin complex 2 promotes macrophage activation and kidney fibrosis

Abstract

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.

Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis

“…Loss of Pink1 in BMDMs results in greater mitochondrial-derived superoxide production after TGF-β1 treatment. Previous studies have identified critical roles of rictor (28,29,44) and mitochondrial-derived ROS (43) in promoting macrophage differentiation toward M2 phenotype. Mitophagy is also demonstrated to regulate the expression of TGF-β1 mRNA in alveolar macrophages (45).…”

“…In addition, both Pink1 -/and Prkn -/-CD11b + monocytes and F4/80 + macrophages isolated from peritoneal cavity also showed higher expression of rictor ( Figure 3D). The increase in the expression of rictor is known to play a critical role in the differentiation of M2 macrophages (28,29). In contrast, loss of either PINK1 or Parkin did not affect the expression of inducible nitric oxide synthase-expressing (iNOS-expressing; 130 kDa) M1 macrophages.…”

Overexpression of Rictor in the injured spinal cord promotes functional recovery in a rat model of spinal cord injury

“…However, previous studies have demonstrated that Rictor/mTORC2 promotes M2 macrophage activation in other diseases, such as infection, kidney fibrosis, and tumor growth 34‐36 . Fortunately, our study for the first time shows that Rictor overexpression promotes M2 macrophage polarization around the lesion after SCI.…”

Yap/Taz mediates mTORC2-stimulated fibroblast activation and kidney fibrosis

“…It has been reported that the mTORC2 pathway is important for promoting the fibrosis process (24,(31)(32)(33). In addition, Yap/Taz is the mechano-transducer that regulates TGF␤1 signaling and renal fibrogenesis (15,16,27,34).…”