The stress-response molecule NR4A1 resists ROS-induced pancreatic β-cells apoptosis via WT1

Zong, Chen; Qin, Dandan; Cong, Yu; Gao, Peng; Chen, Jicui; Lu, Sumei; Zhang, Yuchao; Liu, Yuantao; Yang, Yingfeng; Pu, Ze‐qing; Li, Xia; Fu, Yue; Guan, Qingbo; Wang, Xiangdong

doi:10.1016/j.cellsig.2017.03.012

Cited by 20 publications

(30 citation statements)

References 41 publications

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“…The cells were then incubated for 6 h at 37 °C in 5% CO 2 . The transfection mixture was then removed and replaced with normal growth medium, and then the cells were incubated for an additional 24 h. Western blotting was performed to observe the knockdown efficiency [32] .…”

Section: Methodsmentioning

confidence: 99%

Mst1 deletion attenuates renal ischaemia-reperfusion injury: The role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway

Feng

Zhang

et al. 2019

Redox Biology

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Despite extensive research that has been carried out over the past three decades in the field of renal ischaemia-reperfusion (I/R) injury, the pathogenic role of mitochondrial fission in renal I/R injury is poorly understood. The aim of our study is to investigate the molecular mechanism by which mammalian STE20-like kinase 1 (Mst1) participates in renal I/R injury through modifying mitochondrial fission, microtubule cytoskeleton dynamics, and the GSK3β-p53 signalling pathway. Our data demonstrated that genetic ablation of Mst1 improved renal function, alleviated reperfusion-mediated tubular epithelial cell apoptosis, and attenuated the vulnerability of kidney to I/R injury. At the molecular level, Mst1 upregulation exacerbated mitochondrial damage, as evidenced by reduced mitochondrial potential, increased ROS generation, more cyt-c liberation from mitochondria into the cytoplasm, and an activated mitochondrial apoptotic pathway. Furthermore, we demonstrated that I/R-mediated mitochondrial damage resulted from mitochondrial fission, and the blockade of mitochondrial fission preserved mitochondrial homeostasis in the I/R setting. Functional studies have discovered that Mst1 regulated mitochondrial fission through two mechanisms: induction of Drp1 phosphorylation and enhancement of F-actin assembly. Activated Mst1 promoted Drp1 phosphorylation at Ser616, contributing to Drp1 translocation from the cytoplasm to the surface of the mitochondria. Additionally, Mst1 facilitated F-actin polymerization, contributing to mitochondrial contraction. Finally, we confirmed that Mst1 regulated Drp1 post-transcriptional modification and F-actin stabilization via the GSK3β-p53 signalling pathway. Inhibition of GSK3β-p53 signalling provided a survival advantage for the tubular epithelial cell in the context of renal I/R injury by repressing mitochondrial fission. Collectively, our study identified Mst1 as the primary pathogenesis for the development and progression of renal I/R injury via activation of fatal mitochondrial fission by modulating Drp1 phosphorylation, microtubule cytoskeleton dynamics, and the GSK3β-p53 signalling pathway.

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Section: Methodsmentioning

confidence: 99%

Mst1 deletion attenuates renal ischaemia-reperfusion injury: The role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway

Feng

Zhang

et al. 2019

Redox Biology

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“…Oxidative stress was determined by 8-hydroxy-2-deoxyguanosine (8-OHdG) staining (a biomarker for oxidative stress or a marker for reactive oxygen species (ROS) damage) 58 ; dihydroethidium (DHE) staining (a cell-permeable fluorescent dye, redox indicator), NADPH oxidases ( Nox 1, 2 and 4 ) gene expression and NADPH activity 50,51,59,60 . qPCR (Fast SYBR green master mix kit and 7500 Fast real-time PCR system; Applied Biosystems, Foster City, CA, USA) was performed as reported previously 50,51 .…”

Section: Methodsmentioning

confidence: 99%

Hedgehog Interacting Protein (Hhip) Regulates Insulin Secretion in Mice Fed High Fat Diets

Nchienzia

Liao

Zhao

et al. 2019

Sci Rep

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Hedgehog interacting protein (Hhip) is essential for islet formation and beta-cell proliferation during pancreatic development; abnormally elevated Hhip expression has been linked to human pancreatitis. Here, we investigate the role of Hhip in modulating insulin secretion in adult Hhip mice (Hhip +/− vs. Hhip+/+) fed high fat diets (HFD). Both sexes of HFD-Hhip +/+ mice developed impaired glucose intolerance, that was only ameliorated in male HFD-Hhip +/− mice that had high levels of circulating plasma insulin, but not in female HFD-Hhip +/− mice. HFD stimulated Hhip gene expression, mainly in beta cells. Male HFD-Hhip +/+ mice had more large islets in which insulin content was reduced; islet architecture was disordered; and markers of oxidative stress (8-OHdG and Nox 2) were increased. In contrast, male HFD-Hhip +/− mice had more small islets with increased beta cell proliferation, enhanced GSIS, less oxidative stress and preserved islet integrity. In vitro , recombinant Hhip increased Nox2 and NADPH activity and decreased insulin-positive beta cells. siRNA-Hhip increased GSIS and abolished the stimulation of sodium palmitate (PA)-BSA on Nox2 gene expression. We conclude that pancreatic Hhip gene inhibits insulin secretion by altering islet integrity and promoting Nox2 gene expression in beta cells in response to HDF-mediated beta cell dysfunction, a novel finding.

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“…When pro-apoptotic Bcl-2 proteins accumulate, they translocate to the mitochondria and form pores in the mitochondrial membrane. This causes cytochrome c release, caspase-9 activation and eventual cell death [106,107,108]. Understanding how the Nr4a receptor family regulate these pathways will be addressed.…”

Section: Apoptosismentioning

confidence: 99%

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

Herring

Elison

Tessem

2019

Cells

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The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. While currently defined as ligandless, these transcription factors have been shown to regulate varied processes across a host of tissues. Of particular interest, the Nr4a family impinge, in a tissue dependent fashion, on cellular proliferation, apoptosis and fuel utilization. The regulation of these processes occurs through both nuclear and non-genomic pathways. The purpose of this review is to provide a balanced perspective of the tissue specific and Nr4a family member specific, effects on cellular proliferation, apoptosis and fuel utilization.

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The stress-response molecule NR4A1 resists ROS-induced pancreatic β-cells apoptosis via WT1

Cited by 20 publications

References 41 publications

Mst1 deletion attenuates renal ischaemia-reperfusion injury: The role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway

Mst1 deletion attenuates renal ischaemia-reperfusion injury: The role of microtubule cytoskeleton dynamics, mitochondrial fission and the GSK3β-p53 signalling pathway

Hedgehog Interacting Protein (Hhip) Regulates Insulin Secretion in Mice Fed High Fat Diets

Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues

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