NR4A1 silencing protects against renal ischemia-reperfusion injury through activation of the β-catenin signaling pathway in old mice

Shi, Wenjian; Dong, Jing; Liang, Yumei; Liu, Kanghan; Peng, Youming

doi:10.1016/j.yexmp.2019.104303

Cited by 13 publications

(7 citation statements)

References 33 publications

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“…12 Another study has demonstrated that NR4A1 knockdown ameliorates renal I/R damage via activating β-catenin signalling pathway. 34 Moreover, our study suggested that inhibition of NR4A1 protected against I/R damage in mice, supported by reductions in ALT and AST levels and down-regulation of TNFα and IL-1β. Ischaemic injury has indicated to be associated with systemic inflammation because of cytokine production and increased expression of adhesion molecules by hypoxic parenchymal and endothelial cells.…”

Section: Discussionmentioning

confidence: 51%

“…A recent study has reported that the silencing of NR4A1 elevates Mfn2 via the MAPK‐ERK‐CREB signalling pathway which ultimately reverses the cerebral I/R injury 12 . Another study has demonstrated that NR4A1 knockdown ameliorates renal I/R damage via activating β‐catenin signalling pathway 34 . Moreover, our study suggested that inhibition of NR4A1 protected against I/R damage in mice, supported by reductions in ALT and AST levels and down‐regulation of TNF‐α and IL‐1β.…”

Section: Discussionmentioning

confidence: 99%

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NR4A1 knockdown confers hepatoprotection against ischaemia‐reperfusion injury by suppressing TGFβ1 via inhibition of CYR61/NF‐κB in mouse hepatocytes

Cao

Zhou

et al. 2021

J Cellular Molecular Medi

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

NR4A1 knockdown confers hepatoprotection against ischaemia‐reperfusion injury by suppressing TGFβ1 via inhibition of CYR61/NF‐κB in mouse hepatocytes

Cao

Zhou

et al. 2021

J Cellular Molecular Medi

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“…Recent studies have shown that NR4A1 is closely related to IRI in multiple tissues/organs. The expression of NR4A1 was upregulated both in mouse liver tissue treated with IRI and microglia after cerebral IRI indicates that NR4A1 contributes to the promotion of IRI [ 6 , 8 ]. In addition, NR4A1 aggravates cardiac microvascular IRI through suppressing Fundc1-mediated mitochondrial autophagy [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Data from several studies suggest the critical role of NR4A1 in ischemic injury of organs. For instance, in cerebral ischemic injury, NR4A1 could promote the cerebral ischemic injury through regulating nuclear factor-κB (NF-κB) pathway [ 6 ]. In renal ischemic injury, NR4A1 silencing significantly improved the renal IRI in mice by activating β-catenin [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Nuclear receptor 4A1 (NR4A1) silencing protects hepatocyte against hypoxia-reperfusion injury in vitro by activating liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling

Zheng

Tao²,

Zhan

et al. 2022

Bioengineered

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The nuclear receptor 4A1 (NR4A1) is widely involved in the regulation of cell survival and is related to ischemic injury in several organs. This research examined the emerging role and mechanism of NR4A1 in hepatocyte ischemia-reperfusion injury (IRI). BRL-3A cells were subjected to hypoxia-reperfusion (H/R) to simulate an IRI model in vitro . The expression of NR4A1 and liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway-related proteins (LKB1, AMPK, and ACC) was detected by western blotting or RT-qPCR under H/R condition after NR4A1 overexpression or silencing. Then, radicicol, an inhibitor of LKB1 pathway, was used to determine the role of NR4A1 in hepatocyte H/R injury by regulating LKB1. Under the help of CCK-8 assay, cell viability was assessed. The levels of ROS, MDA, and SOD were determined with corresponding kits to evaluate oxidative stress. Additionally, RT-qPCR was employed to analyze the releases of the inflammatory factors. Flow cytometry was applied to estimate the apoptosis and its related proteins, and autophagy-associated proteins were assayed by western blotting. Results indicated that NR4A1 was highly expressed, while proteins in LKB1/AMPK signaling was downregulated in BRL-3A cells exposed to H/R. The activation of LKB1/AMPK pathway could be negatively regulated by NR4A1. Moreover, NR4A1 depletion conspicuously promoted cell viability, inhibited oxidative stress as well as inflammation, and induced apoptosis and autophagy in H/R-stimulated BRL-3A cells, which were reversed after radicicol intervention. Collectively, NR4A1/LKB1/AMPK axis is a new protective pathway involved in hepatocyte IRI, shedding new insights into the improvement of hepatocyte IRI.

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“…And Nr4a1 also plays a facilitating role in mediating TGFβ-induced lung cancer cells invasion and embryonal rhabdomyosarcoma cells invasion (12,13). In the eld of renal disease, it has been reported that silencing Nr4a1 ameliorates renal ischemia-reperfusion injury (IRI) (14). And in diabetic nephropathy, higher Nr4a1 expression was related to renal brosis and glomerular apoptosis, mediating high glucose-induced mitochondrial damage in human renal mesangial cells (15).…”

Section: Introductionmentioning

confidence: 99%

Nr4a1 promotes renal interstitial fibrosis by regulating the p38 MAPK phosphorylation

Tao

Tang

Wei

et al. 2022

Preprint

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Background Renal interstitial fibrosis (RIF) is a common pathological change in kidney diseases progressing into end-stage renal disease and involves multiple cell types, but the key targets and regulatory mechanisms have not been fully elucidated. Nuclear receptor subfamily 4 group A member 1(Nr4a1) belongs to a subfamily of nuclear receptors, and in this study, we found a regulatory effect of Nr4a1 on p38 MAPK phosphorylation in renal tubular epithelial cells with renal interstitial fibrosis. Methods Firstly, we collected human renal fibrosis specimens and used unilateral ureteral obstruction (UUO) mice and transforming growth factor (TGF)-β1-stimulated human renal proximal tubular epithelial cells (HK-2) as in vivo and in vitro models to detect the expression of Nr4a1. Subsequently, using Nr4a1-specific agonist Cytosporone B (Csn-B) in vivo and in vitro and Nr4a1 small interfering RNA in vitro, we observed renal pathological changes by HE and Masson staining, and immunohistochemical staining and western blot were performed to detect the expression of fibronectin (Fn) and collagen-I (Col-I), as well as p38 MAPK phosphorylation level. Results The results showed that firstly Nr4a1 expression was upregulated in human fibrosis and UUO mice kidney, and positively correlated with the degree of interstitial kidney injury and fibrotic protein expression. Csn-B aggravated UUO-caused renal interstitial fibrosis and activated p38 MAPK phosphorylation. In vitro it also showed that Nr4a1 expression increased under TGF-β1 stimulation, and transfection with Nr4a1 small interfering RNA reduced the expression of TGF-β1-stimulated Fn、Col-I and p38 MAPK phosphorylation levels. Similary, Csn-B induced Fn、Col-I expression and p38 MAPK phosphorylation in HK-2 cells. Further, p38 MAPK inhibitor SB203580 reversed the Csn-B-induced Fn and Col-I expression. In addition, immunofluorescence and western blot suggested that Csn-B induced increased Nr4a1 expression in the cytoplasm. Conclusion The above results indicated that Nr4a1 could exert pro-fibrotic effect by regulating p38 MAPK phosphorylation in renal interstitial fibrosis.

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NR4A1 silencing protects against renal ischemia-reperfusion injury through activation of the β-catenin signaling pathway in old mice

Cited by 13 publications

References 33 publications

NR4A1 knockdown confers hepatoprotection against ischaemia‐reperfusion injury by suppressing TGFβ1 via inhibition of CYR61/NF‐κB in mouse hepatocytes

NR4A1 knockdown confers hepatoprotection against ischaemia‐reperfusion injury by suppressing TGFβ1 via inhibition of CYR61/NF‐κB in mouse hepatocytes

Nuclear receptor 4A1 (NR4A1) silencing protects hepatocyte against hypoxia-reperfusion injury in vitro by activating liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling

Nr4a1 promotes renal interstitial fibrosis by regulating the p38 MAPK phosphorylation

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