Copper affects the binding of HIF-1α to the critical motifs of its target genes

Wu, Zhijuan; Zhang, Wenjing; Kang, Y. James

doi:10.1039/c8mt00280k

Cited by 59 publications

(57 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, our study demonstrated that HIF-1α-BNIP3-mediated mitophagy protects against AKI by reducing apoptosis of renal tubular cells. The present finding that HIF-1α directly increased the transcription and expression of BNIP3 is consistent with previous studies demonstrating that HIF-1α plays a critical role in hypoxia-induced mitophagy [ 43 ], and that BNIP3 acts as a direct downstream regulator of HIF-1α in hypoxia [ 44 ].…”

Section: Discussionsupporting

confidence: 93%

HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury

et al. 2020

View full text Add to dashboard Cite

In the present study, we hypothesized that hypoxia-inducible factor 1α (HIF-1α)-mediated mitophagy plays a protective role in ischemia/reperfusion (I/R)-induced acute kidney injury (AKI). Mitophagy was evaluated by measuring the changes of mitophagy flux, mitochondria DNA copy number, and the changes of mitophagy-related proteins including translocase of outer mitochondrial membrane 20 (TOMM20), cytochrome c oxidase IV (COX IV), microtubule-associated protein 1 light chain 3B (LC3B), and mitochondria adaptor nucleoporin p62 in HK2 cells, a human tubular cell line. Results show that HIF-1α knockout significantly attenuated hypoxia/reoxygenation (H/R)-induced mitophagy, aggravated H/R-induced apoptosis, and increased the production of reactive oxygen species (ROS). Similarly, H/R induced significantly increase in Bcl-2 19-kDa interacting protein 3 (BNIP3), a downstream regulator of HIF-1α. Notably, BNIP3 overexpression reversed the inhibitory effect of HIF-1α knockout on H/R-induced mitophagy, and prevented the enhancing effect of HIF-1α knockout on H/R-induced apoptosis and ROS production. For in vivo study, we established HIF-1α flox/flox ; cadherin-16-cre mice in which tubular HIF-1α was specifically knockout. It was found that tubular HIF-1α knockout significantly inhibited I/R-induced mitophagy, and aggravated I/R-induced tubular apoptosis and kidney damage. In contrast, adenovirus-mediated BNIP3 overexpression significantly reversed the decreased mitophagy, and prevented enhanced kidney damage in tubular HIF-1α knockout mice with I/R injury. In summary, our study demonstrated that HIF-1α-BNIP3-mediated mitophagy in tubular cells plays a protective role through inhibition of apoptosis and ROS production in acute kidney damage.

show abstract

Section: Discussionsupporting

confidence: 93%

HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that hypoxia-inducible factor-1α (HIF-1α), a transcription factor closely related to the oxygen concentration in vivo, was the key of the puzzle [5][6][7]. The regulation of HIF-1α and its target genes has provided a framework for beginning to understand the neuroprotective mechanism of HPC [8,9].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat

Wang

et al. 2020

Neurosurg Rev

View full text Add to dashboard Cite

Hypoxia preconditioning (HPC), a well-established preconditioning model, has been shown to protect the brain against severe hypoxia or ischemia caused by traumatic brain injury (TBI), but the mechanism has not been well elucidated. Anaerobic glycolysis is the major way for neurons to produce energy under cerebral ischemia and hypoxia after TBI, and it requires large amounts of glucose. We hypothesized that glucose transport, as a rate-limiting step of glucose metabolism, may play key roles in the neuroprotective effects of HPC on cerebral cortex tissue against TBI. The aim of this study was to investigate the effect of HPC on glucose transport activity of rat cerebral cortex tissue after TBI through examining the gene expression of two major glucose transporters (GLUT1 and GLUT3) and their upstream target gene hypoxia-inducible factor-1α (HIF-1α). Sprague-Dawley rats were treated with HPC (50.47 kPa, 3 h/d, 3d). Twenty-four hours after the last treatment, the rats were injured using the Feeney free falling model. Cortex tissues of injured rats were removed at 1 h, 4 h, 8 h, 12 h, 1 day, 3 days, 7 d, and 14 days post-injury for histological analysis. Compared with TBI alone, HPC before TBI resulted in the expression of HIF-1α, GLUT1, and GLUT3 to increase at 1 h; they were markedly increased at 4 h, 8 h, 12 h, 1 day, and 3 days and decreased thereafter (p < 0.05). HPC before TBI could improve neuronal survival in rats by examining NeuN staining and observing reduced apoptosis by examining TUNEL staining. The result showed that HPC before TBI could increase the expression of GLUT1 and GLUT3. And through double immunofluorescence staining for GLUT3 and NeuN, the results strongly suggest that HPC improved glucose transport activity of neurons in rats with TBI. In summary, our results further support that HPC can improve hypoxia tolerance and attenuate neuronal loss of cerebral cortex in rats after TBI. The mechanism is mainly related to the increase of glucose transport activity through inducing GLUT1 and GLUT3 expression through upregulating HIF-1α expression.

show abstract

“…Significantly, copper can either directly or indirectly influence different proangiogenetic pathways. In particular, copper can bind angiogenin promoting its biological activity to stimulate formation of blood vessels [114]; moreover, copper is required for the binding of hypoxia-inducible factor (HIF-1) to the hypoxia-response elements, thus modulating expression of some key proangiogenic factors [115], such as vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), interleukin (IL)-1α and IL-8 ( Figure 1).…”

Section: Copper Chelation and Tumor Angiogenesismentioning

confidence: 99%

Current Biomedical Use of Copper Chelation Therapy

Baldari

Rocco

Toietta

2020

IJMS

124

105

View full text Add to dashboard Cite

Copper is an essential microelement that plays an important role in a wide variety of biological processes. Copper concentration has to be finely regulated, as any imbalance in its homeostasis can induce abnormalities. In particular, excess copper plays an important role in the etiopathogenesis of the genetic disease Wilson’s syndrome, in neurological and neurodegenerative pathologies such as Alzheimer’s and Parkinson’s diseases, in idiopathic pulmonary fibrosis, in diabetes, and in several forms of cancer. Copper chelating agents are among the most promising tools to keep copper concentration at physiological levels. In this review, we focus on the most relevant compounds experimentally and clinically evaluated for their ability to counteract copper homeostasis deregulation. In particular, we provide a general overview of the main disorders characterized by a pathological increase in copper levels, summarizing the principal copper chelating therapies adopted in clinical trials.

show abstract

Copper affects the binding of HIF-1α to the critical motifs of its target genes

Abstract: Copper regulates the target gene selection of HIF-1α under hypoxic conditions by affecting HIF-1α-DNA binding patterns across the genome.

Cited by 59 publications

References 55 publications

HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury

HIF-1α-BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury

Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat

Current Biomedical Use of Copper Chelation Therapy

Contact Info

Product

Resources

About