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

Abstract

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.

Hypoxic/Ischemic Inflammation, MicroRNAs and δ-Opioid Receptors: Hypoxia/Ischemia-Sensitive Versus-Insensitive Organs

“…DOR is present not only in the nervous system but also in other organs such as the heart, lungs, liver, and gastrointestinal and reproductive tracts ( Feng et al, 2012 ). Our recent studies as well as those of others present strong evidence of the DOR-mediated cyto-protection in different organs, including brain, kidney, heart, and liver ( Zhang et al, 2000 , 2002 , 2006 ; Ma et al, 2005 ; Chao et al, 2007 , 2008 , 2009 , 2012 ; Kang et al, 2009 ; Chao and Xia, 2010 ; Feng et al, 2011 , 2012 ; He et al, 2013a ; Luo et al, 2019 ). Moreover, there is accumulating evidence that DOR activation can achieve a protective role against H/I injury by modulating miRNA expression in multiple organs ( Yang et al, 2012 ; He et al, 2013b ; Zhi et al, 2016 , 2017 ), especially in the process of neuroinflammation ( Chen et al, 2020c ).…”

Alleviation of TGF‐β1 induced tubular epithelial–mesenchymal transition via the δ‐opioid receptor

“…NRK‐52E cells were obtained from Chinese Academy of Sciences. Cell culture and drug treatment were performed as previously described [59]. Recombinant TGF‐β1 was acquired from Peprotech, Inc. (Rocky Hill, NJ, USA).…”

“…Cells were harvested and performed by western blotting as we did before [59,62]. The antibodies against β‐actin, α‐SMA, P‐Smad3, Smad3, Snail, P‐Akt, Akt, P‐p38, and p38 were purchased from Cell Signaling Technologies (Danvers, MA, USA).…”

δ-opioid Receptor, Microglia and Neuroinflammation

“…Interestingly, DOR, being less important in pain control compared to MOR with a low abuse liability [9], shows a unique potential in neuroprotection and inflammatory regulation. DOR activation or overexpression can effectively protect the neurons against several injuries, including hypoxic/ischemic injury and neurodegenerative injury [10][11][12][13][14][15][16][17][18], and these protective effects are closely associated with DOR's interaction with several intracellular compartments and regulation of inflammatory cytokines through mitogen-activated protein kinases (MAPKs), Nrf2 and PI3K/Akt pathways [19][20][21]. Indeed, DORmediated neuroprotection has been well documented in primary cultured neurons, brain slices, and animal brains in vivo [8].…”