A novel mechanism for cytoprotection against hypoxic injury: δ‐opioid receptor‐mediated increase in <scp>N</scp>rf2 translocation

Cao, Shan; Chao, Dongman; Zhou, Hong‐Hao; Balboni, Gianfranco; Xia, Ying

doi:10.1111/bph.13031

Cited by 37 publications

(32 citation statements)

References 52 publications

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“…A current study using absolute quantitative real-time illustrated that the kidney is principally a "DOR organ" since DOR expression is approximately 44.5-fold higher than that of KOR, without any detectable expression of MOR (Peng et al, 2012). Indeed, our studies (Chen et al, 2014;Cao et al, 2015) have shown DOR expression at both mRNA and protein levels in HEK293 cells. We have also found that DOR activation can modify microRNA expression in rat kidney under prolonged hypoxia (He et al, 2013b), suggesting an important role of DOR in renal adaptation to hypoxic stress.…”

Section: Discussionmentioning

confidence: 55%

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

Luo

Song

et al. 2020

Front. Physiol.

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Hypoxic injury is one of the most important factors in progressive kidney disorders. Since we have found that δ-opioid receptor (DOR) is neuroprotective against hypoxic stress through a differential regulation of mitogen-activated protein kinases (MAPKs) and anti-inflammatory cytokines, we asked if DOR that is highly expressed in the kidney can modulate renal MAPKs and anti-inflammatory cytokines under hypoxia. We exposed cultured rat kidney epithelial cells (NRK-52E) to prolonged hypoxia (1% O 2) with applications of specific DOR agonist or/and antagonist to examine if DOR affects hypoxia-induced changes in MAPKs and anti-inflammatory cytokines. The results showed that endogenous DOR expression remained unchanged under hypoxia, while DOR activation with UFP-512 (a specific DOR agonist) reversed the hypoxia-induced up-regulation of ERK1/2 and p38 phosphorylation. DOR inhibition with naltrindole had no appreciable effect on the hypoxia-induced changes in ERK1/2 phosphorylation, but increased p38 phosphorylation. DOR inhibition with naltrindole attenuated the effects of DOR activation on the changes in ERK1/2 and p38 phosphorylation in hypoxia. Moreover, DOR activation/inhibition differentially affected the expression of transcriptional repressor B-cell lymphoma 6 (Bcl-6), anti-inflammatory cytokines tristetraprolin (TTP), and interleukin-10 (IL-10). Taken together, our novel data suggest that DOR activation differentially regulates ERK1/2, p38, Bcl-6, TTP, and IL-10 in the renal cells under hypoxia.

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Section: Discussionmentioning

confidence: 55%

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

Luo

Song

et al. 2020

Front. Physiol.

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“…Furthermore, we explored whether Nrf-2 was involved in the response of the kidney epithelial cells to hypoxia by detecting its protein level in nuclear proteins because its translocation and function were reported as a cytoprotective strategy against hypoxic injury in astrocytes and other cells. 28 Similarly, the Nrf-2 protein had no significant change after hypoxic exposure for 24 to 72 h ( Fig. 5 ), suggesting that Nrf-2 is unlikely to be involved in the tolerance of the kidney epithelial cells to hypoxic stress.…”

Section: Resultsmentioning

confidence: 86%

ERK and p38 Upregulation versus Bcl-6 Downregulation in Rat Kidney Epithelial Cells Exposed to Prolonged Hypoxia

Luo

Shi

et al. 2017

Cell Transplant

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Hypoxia is a common cause of kidney injury and a major issue in kidney transplantation. Mitogen-activated protein kinases (MAPKs) are involved in the cellular response to hypoxia, but the precise roles of MAPKs in renal cell reactions to hypoxic stress are not well known yet. This work was conducted to investigate the regulation of extracellular signal-regulated kinase-1 and -2 (ERK1/2) and p38 and their signaling-relevant molecules in kidney epithelial cells exposed to prolonged hypoxia. Rat kidney epithelial cells Normal Rat Kidney (NRK)-52E were exposed to hypoxic conditions (1% O2) for 24 to 72 h. Cell morphology was examined by light microscopy, and cell viability was checked by 3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxypheny]-2-[4-sulfophenyl]-2H-tetrazolium (MTS). The expression of ERK1/2 and p38 MAPK, as well as their signaling-related molecules, was measured by Western blot and real-time polymerase chain (RT-PCR) reaction. At the 1% oxygen level, cell morphology had no appreciable changes compared to the control up to 72 h of exposure under light microscopy, whereas the results of MTS showed a slight but significant reduction in cell viability after 72 h of hypoxia. On the other hand, ERK1/2 and p38 phosphorylation remarkably increased in these cells after 24 to 72 h of hypoxia. In sharp contrast, the expression of transcription factor B-cell lymphoma 6 (Bcl-6) was significantly downregulated in response to hypoxic stress. Other intracellular molecules relevant to the ERK1/2 and p38 signaling pathway, such as protein kinase A, protein kinase C, Bcl-2, nuclear factor erythroid 2-related factor 2, tristetraprolin, and interleukin-10(IL-10), had no significant alterations after 24 to 72 h of hypoxic exposure. We conclude that hypoxic stress increases the phosphorylation of both ERK1/2 and p38 but decreases the level of Bcl-6 in rat kidney epithelial cells.

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“…It has previously been reported that DADLE activates the DOR, thus resulting in DOR-associated neuronal protection, via PKC (34). In addition, Cao et al (35) demonstrated that signal transduction via the DOR-PKC-Nrf2 pathway may exert a protective effect against cell hypoxia-reoxygenation injury. The present study indicated that the protein expression levels of total Nrf2 were higher in the I/R, DADLE and N/D groups compared with in the Sham group; however, this finding was not significant.…”

Section: Discussionmentioning

confidence: 99%

DADLE improves hepatic ischemia/reperfusion injury in mice via activation of the Nrf2/HO-1 pathway

Zhou

Zhang

Lei

et al. 2017

Molecular Medicine Reports

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Hepatic ischemia/reperfusion (I/R) injury is a common pathophysiological process that occurs following liver surgery, which is associated with oxidative stress, and can cause acute liver injury and lead to liver failure. Recently, the development of drugs for the prevention of hepatic I/R injury has garnered interest in the field of liver protection research. Previous studies have demonstrated that [D‑Ala2, D‑Leu5]‑Enkephalin (DADLE) exerts protective effects against hepatic I/R injury. To further clarify the specific mechanism underlying the effects of DADLE on hepatic I/R injury, the present study aimed to observe the effects of various doses of DADLE on hepatic I/R injury in mice. The results indicated that DADLE, at a concentration of 5 mg/kg, significantly reduced the levels of alanine aminotransferase and aspartate aminotransferase in the serum, and the levels of malondialdehyde in the liver homogenate. Conversely, the levels of glutathione, catalase and superoxide dismutase in the liver homogenate were increased. In addition, DADLE was able to promote nuclear factor, erythroid 2 like 2 (Nrf2) nuclear translocation and upregulate the expression of heme oxygenase (HO)‑1, which is a factor downstream of Nrf2, thus improving hepatic I/R injury in mice. In conclusion, the present study demonstrated that DADLE was able to significantly improve hepatic I/R injury in mice, and the specific mechanism may be associated with the Nrf2/HO‑1 signaling pathway.

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A novel mechanism for cytoprotection against hypoxic injury: δ‐opioid receptor‐mediated increase in Nrf2 translocation

Cited by 37 publications

References 52 publications

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

The δ-Opioid Receptor Differentially Regulates MAPKs and Anti-inflammatory Cytokines in Rat Kidney Epithelial Cells Under Hypoxia

ERK and p38 Upregulation versus Bcl-6 Downregulation in Rat Kidney Epithelial Cells Exposed to Prolonged Hypoxia

DADLE improves hepatic ischemia/reperfusion injury in mice via activation of the Nrf2/HO-1 pathway

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