Roles for VEGF‐C/NRP–2 axis in regulating renal tubular epithelial cell survival and autophagy during serum deprivation

Chang, Xiaoyan; Yang, Qian; Zhang, Conghui; Zhang, Ying; Liang, Xiaofeng; Liu, Yanyan; Xu, Gang

doi:10.1002/cbf.3402

Cited by 10 publications

(3 citation statements)

References 37 publications

(93 reference statements)

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“…In 2013, Stanton et al discovered for the first time that VEGF-C/NRP-2 axis-activated autophagy helps tumor cells resist treatment 45 . Until recently, our team reported that the VEGF-C/NRP-2 axis can regulate renal tubular epithelial cell autophagy to repair damage 46 . While VEGFR3 is a coreceptor for NRP-2 47 , the present study reported for the first time that VEGF-C/VEGFR3 regulated macrophage autophagy, which in turn affected macrophage polarization and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

Zhang

et al. 2021

Cell Death Dis

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Inflammation plays a crucial role in the occurrence and development of renal fibrosis, which ultimately results in end-stage renal disease (ESRD). There is new focus on lymphangiogenesis in the field of inflammation. Recent studies have revealed the association between lymphangiogenesis and renal fibrosis, but the source of lymphatic endothelial cells (LECs) is not clear. It has also been reported that macrophages are involved in lymphangiogenesis through direct and indirect mechanisms in other tissues. We hypothesized that there was a close relationship between macrophages and lymphatic endothelial progenitor cells in renal fibrosis. In this study, we demonstrated that lymphangiogenesis occurred in a renal fibrosis model and was positively correlated with the degree of fibrosis and macrophage infiltration. Compared to resting (M0) macrophages and alternatively activated (M2) macrophages, classically activated (M1) macrophages predominantly transdifferentiated into LECs in vivo and in vitro. VEGF-C further increased M1 macrophage polarization and transdifferentiation into LECs by activating VEGFR3. It was suggested that VEGF-C/VEGFR3 pathway activation downregulated macrophage autophagy and subsequently regulated macrophage phenotype. The induction of autophagy in macrophages by rapamycin decreased M1 macrophage polarization and differentiation into LECs. These results suggested that M1 macrophages promoted lymphangiogenesis and contributed to newly formed lymphatic vessels in the renal fibrosis microenvironment, and VEGF-C/VEGFR3 signaling promoted macrophage M1 polarization by suppressing macrophage autophagy and then increased the transdifferentiation of M1 macrophages into LECs.

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Section: Discussionmentioning

confidence: 99%

Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

Zhang

et al. 2021

Cell Death Dis

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“…These results suggest that resident macrophages not only phagocytose the environment but also respond rapidly to the environment and release cytokines. VEGF-C is a classic lymphatic growth factor produced by circulating macrophages, podocytes and tubule epithelial cells (40)(41)(42). It promotes expansion and reconstruction of the lymphatic capillary net through activation of VEGFR-3 on LECs, leading to lymphangiogenesis in chronic kidney diseases.…”

Section: Discussionmentioning

confidence: 99%

CD137L-macrophage induce lymphatic endothelial cells autophagy to promote lymphangiogenesis in renal fibrosis

Huang¹,

Chen²,

Li³

et al. 2022

Int. J. Biol. Sci.

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Renal lymphangiogenesis is a new field of international nephrology in recent years and plays an important role in the progression of chronic renal disease. CD137 was originally described as a surface molecule present on activated T and NK cells and detected on hypoxic endothelial cells and inflamed blood vessels, but its function on lymphatic endothelial cells remains unclear. We investigated the relationships among CD137, lymphangiogenesis and macrophages, which are involved in interstitial fibrosis. Similar to other chronic inflammatory diseases, we found lymphangiogenesis and expression of CD137 in the renal tissue of patients with IgA nephropathy. CD137-positive lymphatic vessels were involved in the development process of IgA nephropathy and positively correlated with serum creatinine, serum urea nitrogen, serum uric acid, and urinary 24 h total protein. The expression of these indicators was negatively correlated with eGFR, plasma albumin, and HB. In mouse models of UUO, we verified that CD137 expression was significantly elevated during lymphangiogenesis and that its ligand CD137L was released by macrophages after VEGF-C stimulation in the kidney. In vitro, recombinant CD137L significantly enhanced LEC proliferation, migration and tube formation, and these effects were inhibited by CD137 siRNA. Mechanistically, the CD137L interaction with CD137 induced the transition from LC3-I to LC3-II and the expression of Atg5, Atg7, Atg12 and p62 proteins by activating the PI3K/AKT/mTOR pathway to promote autophagy. Knockdown of Atg5 and Atg7 blocked CD137L-induced autophagy. Thus, we propose that CD137L secretion by macrophages interacts with CD137 on lymphatic endothelial cells to prompt lymphangiogenesis in the kidney, which further drives fibrogenic responses. Our findings suggest that inhibition of the CD137-CD137L pathway is a novel therapeutic approach for obstructive nephropathy.

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“…For a start, the mechanisms by which VEGF-A inhibition and VEGF-C therapy act and the relative contribution of these therapies to different cell types in the polycystic kidney is unknown. For example, to what extent VEGF-C might exert its effects on non-endothelial cell types, such as macrophages [82] or tubular epithelial cells [83] in the context of cystic disease is not clear. These could be teased out by transcriptomic technologies capable of differentiating between cell types, such as single cell RNA-sequencing [84].…”

Section: Future Directionsmentioning

confidence: 99%

Endothelial-epithelial communication in polycystic kidney disease: Role of vascular endothelial growth factor signalling

Perretta-Tejedor

Jafree

Long

2020

Cellular Signalling

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Whereas targeting the cyst epithelium and its molecular machinery has been the prevailing clinical strategy for polycystic kidney disease, the endothelium, including blood vasculature and lymphatics, is emerging as an important player in this disorder. In this Review, we provide an overview of the structural and functional alterations to blood vasculature and lymphatic vessels in the polycystic kidney. We also discuss evidence for vascular endothelial growth factor signalling, otherwise critical for endothelial cell development and maintenance, as being a fundamental molecular pathway in polycystic kidney disease and a potential therapeutic target for modulating cyst expansion.

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Roles for VEGF‐C/NRP–2 axis in regulating renal tubular epithelial cell survival and autophagy during serum deprivation

Cited by 10 publications

References 37 publications

Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

Lymphangiogenesis in renal fibrosis arises from macrophages via VEGF-C/VEGFR3-dependent autophagy and polarization

CD137L-macrophage induce lymphatic endothelial cells autophagy to promote lymphangiogenesis in renal fibrosis

Endothelial-epithelial communication in polycystic kidney disease: Role of vascular endothelial growth factor signalling

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