P2Y12 inhibitor clopidogrel inhibits renal fibrosis by blocking macrophage-to-myofibroblast transition

Chen, Junzhe; Tang, Ying; Yu, Zhongbo; Wei, Biao; Huang, Xiao‐Ru; Tang, Patrick Ming‐Kuen; Xu, Anping; Lan, Hui‐Yao

doi:10.1016/j.ymthe.2022.06.019

Cited by 22 publications

(26 citation statements)

References 56 publications

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“…Numerous studies indicate that macrophages are a major contributor to the inflammatory response of AKI ( Huen and Cantley, 2017 ; Martin-Sanchez et al, 2022 ). Macrophage-induced inflammatory and fibrotic responses are also key drivers of renal fibrosis, which will enhance the progression of CKD ( Chen et al, 2022 ; Zhou et al, 2022 ). Responding to tissue damage, macrophages are activated in response to particular signals from the injury microenvironment ( Okubo et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

et al. 2022

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Acute kidney injury (AKI) is a common clinical syndrome with complex pathogenesis, characterized by a rapid decline in kidney function in the short term. Worse still, the incomplete recovery from AKI increases the risk of progression to chronic kidney disease (CKD). However, the pathogenesis and underlying mechanism remain largely unknown. Macrophages play an important role during kidney injury and tissue repair, but its role in AKI-to-CKD transition remains elusive. Herein, single nucleus RNA sequencing (snRNA-Seq) and flow cytometry validations showed that E-type prostaglandin receptor 4 (EP4) was selectively activated in renal macrophages, rather than proximal tubules, in ischemia-reperfusion injury (IRI)-induced AKI-to-CKD transition mouse model. EP4 inhibition aggravated AKI-to-CKD transition, while EP4 activation impeded the progression of AKI to CKD though regulating macrophage polarization. Mechanistically, network pharmacological analysis and subsequent experimental verifications revealed that the activated EP4 inhibited macrophage polarization through inducing Carnitine palmitoyltransferase 2 (CPT2)-mediated lipophagy in macrophages. Further, CPT2 inhibition abrogated the protective effect of EP4 on AKI-to-CKD transition. Taken together, our findings demonstrate that EP4-CPT2 signaling-mediated lipophagy in macrophages plays a pivotal role in the transition of AKI to CKD and targeting EP4-CPT2 axis could serve as a promising therapeutic approach for retarding AKI and its progression to CKD.

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Section: Introductionmentioning

confidence: 99%

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

et al. 2022

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“…In our previous studies, we reported that TGF‐β/Smad3 signaling is a key regulator of the pro‐tumoral microenvironment [ 10,11,22 ] and essential for initiating macrophage‐myofibroblast transition under chronic inflammatory diseases, including cancer. [ 14,18,23,24 ] However, targeting Smad3 would also suppress T‐cell anticancer immunity. [ 25 ] Therefore, we aimed to search for macrophage‐specific TGF‐β/Smad3 signaling by identifying and characterizing its downstream pathogenic mediators as potential therapeutic targets that could specifically block MMT while preserving the anticancer activities of Smad3.…”

Section: Discussionmentioning

confidence: 99%

Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage–Myofibroblast Transition in Non‐Small‐Cell Lung Carcinoma

Tang,

Chan,

Chung

et al. 2023

Advanced Science

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Macrophage‐myofibroblast transition (MMT) is a newly discovered pathway for mass production of pro‐tumoral cancer‐associated fibroblasts (CAFs) in non‐small cell lung carcinoma (NSCLC) in a TGF‐β1/Smad3 dependent manner. Better understanding its regulatory signaling in tumor microenvironment (TME) may identify druggable target for the development of precision medicine. Here, by dissecting the transcriptome dynamics of tumor‐associated macrophage at single‐cell resolution, a crucial role of a hematopoietic transcription factor Runx1 in MMT formation is revealed. Surprisingly, integrative bioinformatic analysis uncovers Runx1 as a key regulator in the downstream of MMT‐specific TGF‐β1/Smad3 signaling. Stromal Runx1 level positively correlates with the MMT‐derived CAF abundance and mortality in NSCLC patients. Mechanistically, macrophage‐specific Runx1 promotes the transcription of genes related to CAF signatures in MMT cells at genomic level. Importantly, macrophage‐specific genetic deletion and systemic pharmacological inhibition of TGF‐β1/Smad3/Runx1 signaling effectively prevent MMT‐driven CAF and tumor formation in vitro and in vivo, representing a potential therapeutic target for clinical NSCLC.

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“…TGF‐β is a cytokine that is abundant in platelets (Assoian et al, 1984) and other cells, and can control many biological and pathological processes, including immunological response, cell proliferation, differentiation, and tissue fibrosis (Yang & Moses, 1990). A previous study has shown that P2Y 12 may mediate renal fibrosis by promoting macrophage‐to‐myofibroblast transition through TGF‐β/Smad3 signalling (Chen et al, 2022). In both cases, a link between P2Y 12 and TGF‐β secretion was noted, but further research is needed to appreciate how blocking P2Y 12 modulates TGF‐β secretion.…”

Section: The P2y12 Receptormentioning

confidence: 99%

Platelet P2Y₁₂ signalling pathway in the dysregulated immune response during sepsis

Amoafo,

Entsie,

Kang

et al. 2023

British J Pharmacology

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Sepsis is a complicated pathological condition in response to severe infections. It is characterized by a strong systemic inflammatory response and multiple components of the immune system are involved. Currently, there is no treatment for sepsis. Platelets are known for their role in hemostasis but they participate in inflammation through cell‐cell interaction and the secretion of inflammatory mediators. Interestingly, an increase in platelet activation, secretion, and aggregation with other immune cells such as monocytes, T lymphocytes, and neutrophils, has been detected in septic patients. Therefore, antiplatelet therapy in terms of P2Y12 antagonists has been evaluated as a possible treatment for sepsis. Overall, blocking P2Y12 decreased platelet marker expression limiting attachment to immune cells in certain studies, but not others. This review underlines the role of platelets during sepsis and whether antagonizing the P2Y12 signaling pathways can alter the outcome. Challenges in studying P2Y12 antagonists in sepsis will also be discussed.

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P2Y12 inhibitor clopidogrel inhibits renal fibrosis by blocking macrophage-to-myofibroblast transition

Cited by 22 publications

References 56 publications

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage–Myofibroblast Transition in Non‐Small‐Cell Lung Carcinoma

Platelet P2Y₁₂ signalling pathway in the dysregulated immune response during sepsis

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P2Y12 inhibitor clopidogrel inhibits renal fibrosis by blocking macrophage-to-myofibroblast transition

Cited by 22 publications

References 56 publications

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

Activation of EP4 alleviates AKI-to-CKD transition through inducing CPT2-mediated lipophagy in renal macrophages

Hematopoietic Transcription Factor RUNX1 is Essential for Promoting Macrophage–Myofibroblast Transition in Non‐Small‐Cell Lung Carcinoma

Platelet P2Y12 signalling pathway in the dysregulated immune response during sepsis

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Platelet P2Y₁₂ signalling pathway in the dysregulated immune response during sepsis