Ablation of endothelial prolyl hydroxylase domain protein‐2 promotes renal vascular remodelling and fibrosis in mice

Wang, Shuo; Zeng, Heng; Chen, Sean T.; Zhou, Lei; Xie, Xue-Jiao; He, Xiaochen; Tao, Yongkang; Tuo, Qin-Hui; Chang-qin, Deng; Liao, Duan‐Fang; Chen, Jianxiong

doi:10.1111/jcmm.13117

Cited by 29 publications

(46 citation statements)

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“…We found that the expression of TGF-β was significantly increased in the PHD2 EC KO mice. Our previous studies have provided evidence that activation of TGF-β signaling pathway may contribute to pericyte differentiation into myofibroblasts and fibrosis in the PHD2 EC KO mice [21,22]. Therefore, increased Ang-2 and TGF-β in the liver tissues may be responsible for hepatic fibrosis in the PHD2 EC KO mice.…”

Section: Discussionmentioning

confidence: 99%

“…In three PHD isoforms, PHD2 is considered as the most important HIF-α-regulating isoform [18][19][20]. Our recent studies indicate the expression of PHD2 in endothelial cells has a critical role in the regulation of vascular remodeling and the development of fibrosis by the mechanism involving in upregulation of HIF-2α expression in lung and kidney [21,22]. Accumulating evidence suggests some of hypoxia-associated genes were not regulated by HIFs, implicating potential HIF-independent pathways that are controlled by prolyl hydroxylase domain (PHD) enzymes [23].…”

Section: Introductionmentioning

confidence: 99%

“…Our data demonstrated that specific deletion of PHD2 in endothelium promoted hepatic steatosis and fibrosis via downregulation of atrial natriuretic peptide (ANP) and upregulation of angiopoietin-2 (Ang-2)/ transforming growth factor-b (TGF-β) in a HIF-2α-independent mechanism. EC KO mice were generated using the Cre-LoxP system as previous described [21,22]. The absence of PHD2 in vascular endothelium was confirmed by western blot analysis using cultured endothelial cells (EC) isolated from PHD2 EC KO mice.…”

Section: Introductionmentioning

confidence: 99%

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Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis

Zhou

Zeng

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Liver disease is a leading cause of high mortality and morbidity worldwide. The aim of the present study is to investigate the regulatory role of prolyl hydroxylase-2 (PHD2)-hypoxia-inducible factor-2a (HIF-2α) axis on nonalcoholic fatty liver disease (NAFLD) and to explore the potential mechanisms by which endothelial (EC)-specific PHD2 deficiency regulates hepatic steatosis and fibrosis. Methods: In the endothelial-specific PHD2 knockout (PHD2^ECKO) mouse fed with normal diet or high fat diet (HFD), liver lipid accumulation and fibrosis were measured by Oil Red O and Masson trichrome staining. The fat and body weight (FW/BW) ratio and glucose tolerance were measured. The expression of HIF-2α, atrial natriuretic peptide (ANP), angiopoietin-2 (Ang-2), and transforming growth factor-b (TGF-β) were analyzed by western blot analysis. Results: The steatosis and fibrosis were significantly increased in the PHD2^ECKO mice. FW/BW ratio was significantly increased in the PHD2^ECKO mice. Moreover, knockout of endothelial PHD2 resulted in an impairment of glucose tolerance in mice. Western blot analysis showed that the expression of HIF-2α in liver tissues was not significantly increased. Interestingly, the expression of ANP was decreased, and Ang-2 and TGF-β levels were significantly increased in the liver of PHD2^ECKO mice. The FW/BW ratio was also significantly increased in the PHD2^ECKO mice fed with HFD for 16 weeks. Feeding HFD resulted in a significant increase in hepatic steatosis in the control PHD2^f/f mice, but did not further enhance hepatic steatosis in the PHD2^ECKO mice. Conclusions: We concluded that the endothelial PHD2 plays a critical role in hepatic steatosis and fibrosis, which may be involved in the regulation of ANP and Ang-2/TGF-β signaling pathway, but not the HIF-2α expression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis

Zhou

Zeng

Wang

et al. 2018

Cell Physiol Biochem

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“…Similar synergistic interaction of HIF and TGF-β1/SMAD3 signalling has also been reported in the regulation of VEGF, endothelin and erythropoietin expression [ 24 ]. Furthermore, accumulation of HIF in the endothelial cells of endothelial specific propyl hydroxylase-2 knockout mice upregulated TGF-β1 expression, resulting in significantly poorer renal function [ 30 ]. In a study using a renal tubular cell line in which transcription of HIF-α was absent, there was a decrease in basal and TGF-β1 stimulated Col-1 expression [ 31 ].…”

Section: Role Of Hypoxia and Hypoxia-inducible Factor (Hif)mentioning

confidence: 99%

Ischaemia reperfusion injury: mechanisms of progression to chronic graft dysfunction

Situmorang

Sheerin

2018

Pediatr Nephrol

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The increasing use of extended criteria organs to meet the demand for kidney transplantation raises an important question of how the severity of early ischaemic injury influences long-term outcomes. Significant acute ischaemic kidney injury is associated with delayed graft function, increased immune-associated events and, ultimately, earlier deterioration of graft function. A comprehensive understanding of immediate molecular events that ensue post-ischaemia and their potential long-term consequences are key to the discovery of novel therapeutic targets. Acute ischaemic injury primarily affects tubular structure and function. Depending on the severity and persistence of the insult, this may resolve completely, leading to restoration of normal function, or be sustained, resulting in persistent renal impairment and progressive functional loss. Long-term effects of acute renal ischaemia are mediated by several mechanisms including hypoxia, HIF-1 activation, endothelial dysfunction leading to vascular rarefaction, sustained pro-inflammatory stimuli involving innate and adaptive immune responses, failure of tubular cells to recover and epigenetic changes. This review describes the biological relevance and interaction of these mechanisms based on currently available evidence.

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“…Although it is evident that PHD deficiency is involved in tissue fibrosis (chapter 2, 6), not much is known about the direct consequence of PHD inhibition in fibroblast-like cells, or how paracrine signaling of PHD deficient cells can change fibroblast behavior. Corroboration of our paracrine signaling model (chapter 6) was given by Wang and colleagues, showing increased pericyte coverage of small blood vessels in kidney and lung tissue of endothelial cell PHD2ko mice [155][156][157]. In addition, pulmonary blood vessel adventitia was enriched with fibroblast-like cells in endothelial cell PHD2ko mice [158].…”

Section: The Increasing Understanding Of Mesenchymal Cell Biology: a mentioning

confidence: 52%

Oxygen Sensors in Atherosclerosis

Demandt¹

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Ablation of endothelial prolyl hydroxylase domain protein‐2 promotes renal vascular remodelling and fibrosis in mice

Cited by 29 publications

References 46 publications

Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis

Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis

Ischaemia reperfusion injury: mechanisms of progression to chronic graft dysfunction

Oxygen Sensors in Atherosclerosis

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