TGF-β promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration

Chung, Sungjin; Overstreet, Jessica M.; Li, Yan; Wang, Yinqiu; Niu, Aolei; Wang, Suwan; Fan, Xiaofeng; Sasaki, Kensuke; Jin, Guan-Nan; Khodo, Stellor Nlandu; Gewin, Leslie; Zhang, Mingzhi; Harris, Raymond C.

doi:10.1172/jci.insight.123563

Cited by 96 publications

(68 citation statements)

References 37 publications

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“…Disruption of pathways involved in macrophage recruitment reduced TGF-β synthesis and attenuated fibrosis in models of acute and chronic fibrotic injury (Dewald et al, 2005;Frangogiannis et al, 2007;Young et al, 2016), suggesting that macrophages are a major source of TGF-β (Juban et al, 2018). In contrast, in models of ischemic and obstructive renal injury, myeloid cell-specific deletion of TGF-β1 did not affect kidney fibrosis (Huen et al, 2013), as other cell types (such as epithelial cells) appeared to serve as a major source of TGF-βs (Chung et al, 2018). Platelets (Meyer et al, 2012), T cell subsets (Celada et al, 2018;Lo Re et al, 2011;Wang et al, 2007), fibroblasts (Nevers et al, 2017), and mast cells (Gordon and Galli, 1994) have also been suggested to represent important sources of TGF-β in various pathophysiological models of tissue fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Transforming growth factor–β in tissue fibrosis

Frangogiannis

2020

Journal of Experimental Medicine

755

454

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TGF-β is extensively implicated in the pathogenesis of fibrosis. In fibrotic lesions, spatially restricted generation of bioactive TGF-β from latent stores requires the cooperation of proteases, integrins, and specialized extracellular matrix molecules. Although fibroblasts are major targets of TGF-β, some fibrogenic actions may reflect activation of other cell types, including macrophages, epithelial cells, and vascular cells. TGF-β–driven fibrosis is mediated through Smad-dependent or non-Smad pathways and is modulated by coreceptors and by interacting networks. This review discusses the role of TGF-β in fibrosis, highlighting mechanisms of TGF-β activation and signaling, the cellular targets of TGF-β actions, and the challenges of therapeutic translation.

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Section: Introductionmentioning

confidence: 99%

Transforming growth factor–β in tissue fibrosis

Frangogiannis

2020

Journal of Experimental Medicine

755

454

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“…TGF-β1, a pluripotent multifunctional and a key profibrogenic cytokine, favors the transdifferentiation of M2 macrophages into myofibroblasts (7,8). Monocyte/ macrophage-specific deletion of TGF-β receptor II has been shown to significantly reduce the infiltration of macrophages and tubulointerstitial fibrosis (9). However, macrophage-specific TGF-β1 deletion failed to prevent kidney fibrosis (10,11).…”

Section: Introductionmentioning

confidence: 99%

Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis

et al. 2019

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“…106 It is noteworthy that TGF-β/Smads play a predominant role in the progression of AKI to CKD. 118 In the tubular injury phase, proximal tubular cells dedifferentiate and proliferate to replace lost epithelial cells. However, when the insult is severe and unresolvable, some cells fail to redifferentiate and continue to produce growth factors such as TGF-β, finally leading to renal fibrosis.…”

Section: Egf and The Egf Receptor In Akimentioning

confidence: 99%

“…119 Additionally, a recent study showed that TGF-βRII deletion in macrophages prevents tubulointerstitial fibrosis following severe ischemic renal injury by abrogating TGFβ-dependent chemoattraction of macrophages. 118 Collectively, the functions of TGF-β/Smads may vary according to their activation level, disease stages, and types of AKI models, which need to be further validated. Exploring the detailed function of TGF-β and downstream Smads may help us to better understand the pathological mechanisms of AKI and its progression to CKD.…”

Section: Egf and The Egf Receptor In Akimentioning

confidence: 99%

Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression

Gao

Zhong

Jin

et al. 2020

Sig Transduct Target Ther

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Acute kidney injury (AKI) is defined as a rapid decline in renal function and is characterized by excessive renal inflammation and programmed death of resident cells. AKI shows high morbidity and mortality, and severe or repeated AKI can transition to chronic kidney disease (CKD) or even end-stage renal disease (ESRD); however, very few effective and specific therapies are available, except for supportive treatment. Growth factors, such as epidermal growth factor (EGF), insulin-like growth factor (IGF), and transforming growth factor-β (TGF-β), are significantly altered in AKI models and have been suggested to play critical roles in the repair process of AKI because of their roles in cell regeneration and renal repair. In recent years, a series of studies have shown evidence that growth factors, receptors, and downstream effectors may be highly involved in the mechanism of AKI and may function in the early stage of AKI in response to stimuli by regulating inflammation and programmed cell death. Moreover, certain growth factors or correlated proteins act as biomarkers for AKI due to their sensitivity and specificity. Furthermore, growth factors originating from mesenchymal stem cells (MSCs) via paracrine signaling or extracellular vesicles recruit leukocytes or repair intrinsic cells and may participate in AKI repair or the AKI-CKD transition. In addition, growth factor-modified MSCs show superior therapeutic potential compared to that of unmodified controls. In this review, we summarized the current therapeutic and diagnostic strategies targeting growth factors to treat AKI in clinical trials. We also evaluated the possibilities of other growth factorcorrelated molecules as therapeutic targets in the treatment of AKI and the AKI-CKD transition.

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TGF-β promotes fibrosis after severe acute kidney injury by enhancing renal macrophage infiltration

Cited by 96 publications

References 37 publications

Transforming growth factor–β in tissue fibrosis

Transforming growth factor–β in tissue fibrosis

Mitophagy-dependent macrophage reprogramming protects against kidney fibrosis

Potential targeted therapy and diagnosis based on novel insight into growth factors, receptors, and downstream effectors in acute kidney injury and acute kidney injury-chronic kidney disease progression

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