Up-Regulation of Early Growth Response Gene-1 Via the CXCR3 Receptor Induces Reactive Oxygen Species and Inhibits Na+/K+-ATPase Activity in an Immortalized Human Proximal Tubule Cell Line

Bek, Martin; Reinhardt, Hans Christian; Fischer, Karl-Georg; Hirsch, Jochen R.; Hupfer, Charlotte; Dayal, Eileen; Pavenstädt, Hermann

doi:10.4049/jimmunol.170.2.931

Cited by 37 publications

(30 citation statements)

References 63 publications

(53 reference statements)

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“…It has been reported that Egr-1 expression is induced by Ca 2+ stimulation and its up-regulation is Ca 2+ -dependent [27,28]. The data from our laboratory suggest that cardioprotection by F 2 is also associated with the inhibition of Ca 2+ overload [4,5] well-documented in I/R injury.…”

Section: Discussionsupporting

confidence: 56%

“…However, in this study overexpression of Egr-1 was in concomitance with high level of TNF-α and low level of SOD. As TNF-α and SOD can be regulated positively and negatively [27] respectively by Egr-1, the results from this study can in turn prove the Egr-1 biological activity. Therefore, with antisense Egr-1 ODN, the present study in vivo and in vitro demonstrated unanimously that overexpression of Egr-1 could be responsible for myocardial I/R injury.…”

Section: Discussionmentioning

confidence: 66%

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The Protective Effects of <i>N</i>-n-butyl Haloperidol Iodide on Myocardial Ischemia-Reperfusion Injury in Rats by Inhibiting Egr-1 Overexpression

Zhang¹,

Shi²,

Zheng

et al. 2007

Cell Physiol Biochem

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Aims: Our previous studies have shown that N-n-butyl haloperidol iodide (F₂) can antagonize myocardial ischemia/reperfusion (I/R) injury by blocking intracellular Ca²⁺ overload. The present study is to test the hypothesis that the protective effects of F₂ on myocardial I/R injury is mediated by downregulating Egr-1 expression. Methods: The Sprague–Dawley rat myocardial I/R model and cardiomyocyte hypoxia/reoxygenation (H/R) model were established. With antisense Egr-1 oligodeoxyribonucleotide (ODN), the relationship between Egr-1 expression and myocardial I/R injury was investigated. Hemodynamic parameters, myeloperoxidase (MPO), cardiac troponin I (cTnI) and tumor necrosis factor-α (TNF-α) were measured to assess the degree of injury and inflammation of myocardial tissues and cells. Egr-1 mRNA and protein expressions were examined by Northern-blot and Western-blot analyses. Results: Treatment with antisense Egr-1 ODN significantly reduced Egr-1 protein expression and attenuated injury of myocardial tissues and cells. Meanwhile, treatment with F₂ significantly inhibited the overexpression of Egr-1 mRNA and protein in myocardial tissues and cells. Consistent with downregulation of Egr-1 expression by F₂, inflammation and other damages were significantly relieved evidenced by the amelioration of hemodynamics, the reduction in myocardial MPO activity as well as the decrease in leakage of cTnI and release of TNF-α from cardiomyocyte. Conclusions: These results suggested that the overexpression of Egr-1 was causative in myocardial I/R or H/R injury, and F₂ could protect myocardial tissues and cells from I/R or H/R injury, which was largely due to the inhibition of Egr-1 overexpresssion.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 66%

The Protective Effects of <i>N</i>-n-butyl Haloperidol Iodide on Myocardial Ischemia-Reperfusion Injury in Rats by Inhibiting Egr-1 Overexpression

Zhang¹,

Shi²,

Zheng

et al. 2007

Cell Physiol Biochem

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“…All of the components necessary for NADPH oxidase to function are present in the kidney, including the presence of four different isoforms of this oxidase-NOX1, NOX2, NOX4, and NOX5 (8,33,112). The expression of these different NADPH oxidase isoform components has been observed throughout the cortex and medulla of the mammalian (including human) kidney, including in the mesangium (97,136,184,190), proximal convoluted tubules, distal convoluted tubules, collecting duct, macula densa (17,77,139,217,281,309,322), endothelium, and VSMCs (8).…”

Section: Nadph Oxidase Rosmentioning

confidence: 99%

Oxidant Mechanisms in Renal Injury and Disease

Ratliff

Abdulmahdi

Pawar

et al. 2016

Antioxidants & Redox Signaling

540

513

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Significance: A common link between all forms of acute and chronic kidney injuries, regardless of species, is enhanced generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) during injury/ disease progression. While low levels of ROS and RNS are required for prosurvival signaling, cell proliferation and growth, and vasoreactivity regulation, an imbalance of ROS and RNS generation and elimination leads to inflammation, cell death, tissue damage, and disease/injury progression. Recent Advances: Many aspects of renal oxidative stress still require investigation, including clarification of the mechanisms which prompt ROS/ RNS generation and subsequent renal damage. However, we currently have a basic understanding of the major features of oxidative stress pathology and its link to kidney injury/disease, which this review summarizes. Critical Issues: The review summarizes the critical sources of oxidative stress in the kidney during injury/ disease, including generation of ROS and RNS from mitochondria, NADPH oxidase, and inducible nitric oxide synthase. The review next summarizes the renal antioxidant systems that protect against oxidative stress, including superoxide dismutase and catalase, the glutathione and thioredoxin systems, and others. Next, we describe how oxidative stress affects kidney function and promotes damage in every nephron segment, including the renal vessels, glomeruli, and tubules. Future Directions: Despite the limited success associated with the application of antioxidants for treatment of kidney injury/disease thus far, preventing the generation and accumulation of ROS and RNS provides an ideal target for potential therapeutic treatments. The review discusses the shortcomings of antioxidant treatments previously used and the potential promise of new ones.

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“…So, very different scenarios are possible for CXCR3-alt function, ranging from accidental irrelevant side product on the one hand to being required for correct CXCR3-full-size function, which has by the way never been shown to be active without CXCR3-alt, in contrast. Further studies focusing on physiological CXCR3 functions in inflammation (5), diseases of lung (16), kidney (17), and CNS (18), and angiostasis and cell proliferation (19,20), will have to scrutinize which functional relevance this novel CXCR3 isoform indeed has.…”

Section: Discussionmentioning

confidence: 99%

Identification and Partial Characterization of a Variant of Human CXCR3 Generated by Posttranscriptional Exon Skipping

Ehlert¹,

Addison

Burdick

et al. 2004

The Journal of Immunology

127

107

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Chemokines are recognized as functionally important in many pathological disorders, which has led to increased interest in mechanisms related to the regulation of chemokine receptor (CKR) expression. Known mechanisms for regulating CKR activity are changes in gene expression or posttranslational modifications. However, little is known about CKR with respect to a third regulatory mechanism, which is observed among other seven-transmembrane receptor subfamilies, the concept of differential splicing or processing of heteronuclear RNA. We now report on the discovery of a variant human CKR, CXCR3, resulting from alternative splicing via exon skipping. The observed RNA processing entails a drastically altered C-terminal protein sequence with a predicted four- or five-transmembrane domain structure, differing from all known functional CKR. However, our data indicate that that this splice variant, which we termed CXCR3-alt, despite its severe structural changes still localizes to the cell surface and mediates functional activity of CXCL11.

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Up-Regulation of Early Growth Response Gene-1 Via the CXCR3 Receptor Induces Reactive Oxygen Species and Inhibits Na+/K+-ATPase Activity in an Immortalized Human Proximal Tubule Cell Line

Cited by 37 publications

References 63 publications

The Protective Effects of <i>N</i>-n-butyl Haloperidol Iodide on Myocardial Ischemia-Reperfusion Injury in Rats by Inhibiting Egr-1 Overexpression

The Protective Effects of <i>N</i>-n-butyl Haloperidol Iodide on Myocardial Ischemia-Reperfusion Injury in Rats by Inhibiting Egr-1 Overexpression

Oxidant Mechanisms in Renal Injury and Disease

Identification and Partial Characterization of a Variant of Human CXCR3 Generated by Posttranscriptional Exon Skipping

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