The Wnt/-catenin pathway is crucial in normal development and throughout life, but aberrant activation of this pathway has been linked to kidney fibrosis, although the mechanisms involved remain incompletely determined. Here, we investigated the role of Wnt/-catenin in regulating macrophage activation and the contribution thereof to kidney fibrosis. Treatment of macrophages with Wnt3a exacerbated IL-4- or TGF1-induced macrophage alternative (M2) polarization and the phosphorylation and nuclear translocation of STAT3 Conversely, inhibition of Wnt/-catenin signaling prevented these IL-4- or TGF1-induced processes. In a mouse model, induced deletion of -catenin in macrophages attenuated the fibrosis, macrophage accumulation, and M2 polarization observed in the kidneys of wild-type littermates after unilateral ureter obstruction. This study shows that activation of Wnt/-catenin signaling promotes kidney fibrosis by stimulating macrophage M2 polarization.

Located in the innermost layer of the vasculature and directly interacting with blood flow, endothelium integrates various biochemical and biomechanical signals to maintain barrier function with selective permeability, vascular tone, blood fluidity, and vascular formation. Endothelial cells respond to laminar and disturbed flow by structural and functional adaption, which involves reprogramming gene expression, cell proliferation and migration, senescence, autophagy and cell death, as well as synthesizing signal molecules (nitric oxide and prostanoids, etc) that act in manners of autocrine, paracrine, or juxtacrine. Inflammation occurs after infection or tissue injury. Dysregulated inflammatory response participates in pathogenesis of many diseases. Endothelial cells exposed to inflammatory stimuli from the circulation or the microenvironment exhibit impaired vascular tone, increased permeability, elevated procoagulant activity, and dysregulated vascular formation, collectively contributing to the development of vascular diseases. Understanding the endothelial response to pathophysiological stress of hemodynamics and inflammation provides mechanistic insights into cardiovascular diseases, as well as therapeutic opportunities.

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Kidney fibrosis is a histological hallmark of chronic kidney disease and arises in large part through extracellular matrix deposition by activated fibroblasts. The signaling protein complex mTOR complex 2 (mTORC2) plays a critical role in fibroblast activation and kidney fibrosis. Protein kinase Cα (PKCα) is one of the major sub-pathways of mTORC2, but its role in fibroblast activation and kidney fibrosis remains to be determined. Here, we found that transforming growth factor β1 (TGFβ1) activates PKCα signaling in cultured NRK-49F cells in a time-dependent manner. Blocking PKCα signaling with the chemical inhibitor Go6976 or by transfection with PKCα siRNA largely reduced expression of the autophagy-associated protein lysosomal-associated membrane protein 2 (LAMP2) and also inhibited autophagosome-lysosome fusion and autophagic flux in the cells. Similarly to chloroquine, Go6976 treatment and PKCα siRNA transfection also markedly inhibited TGFβ1-induced fibroblast activation. In murine fibrotic kidneys with unilateral ureteral obstruction (UUO) nephropathy, PKCα signaling is activated in the interstitial myofibroblasts. Go6976 administration largely blocked autophagic flux in fibroblasts in the fibrotic kidneys and attenuated the UUO nephropathy. Together, our findings suggest that blocking PKCα activity may retard autophagic flux and thereby prevent fibroblast activation and kidney fibrosis.

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.