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KMID : 0620920180500040041
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Experimental & Molecular Medicine
2018 Volume.50 No. 4 p.41 ~ p.41
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The proximal tubular α7 nicotinic acetylcholine receptor attenuates ischemic acute kidney injury through Akt/PKC signaling-mediated HO-1 induction
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Kim Hwa-Jin
Kim So-Ra
Je Ji-Hyun
Jeong Kyu-Ho
Kim Soo-Ji
Kim Hye-Jung
Chang Ki-Churl
Park Sang-Won
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Abstract
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Activation of the α7 nicotinic acetylcholine receptor (α7nAChR) has been shown to attenuate excessive inflammation by inhibiting proinflammatory cytokines during ischemia?reperfusion (IR) injury; however, the underlying kidney-specific molecular mechanisms remain unclear. The protective action of α7nAChR against renal IR injury was investigated using a selective α7nAChR agonist and antagonist. α7nAChR activation reduced plasma creatinine levels and tubular cell damage, whereas α7nAChR inhibition aggravated the IR-induced phenotype. α7nAChR activation decreased neutrophil infiltration and proinflammatory cytokine expression, increased heme oxygenase-1 (HO-1) expression, and reduced proximal tubular apoptosis after IR as shown by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining and caspase-3 cleavage. In this study, we first showed that α7nAChR activation in the proximal tubules induced HO-1 expression through the phosphoinositide 3-kinase (PI3K)/Akt and protein kinase C (PKC) signaling pathway in vivo in renal IR mice and in vitro in proximal tubular cells. Chemical inhibitors of PKC or PI3K/Akt and small interfering RNA-mediated PKC silencing confirmed the signal specificity of α7nAChR-mediated HO-1 induction in the proximal tubular cells. α7nAChR activation inhibited high-mobility group box 1 release by inducing HO-1 expression and reduced proinflammatory cytokine gene expression and apoptotic cell death in tumor necrosis factor α-stimulated proximal tubular cells. Taken together, we conclude that α7nAChR activation in proximal tubular cells directly protects cells against renal IR injury by inducing HO-1 expression through PI3K/Akt and PKC signaling.
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KEYWORD
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Acute inflammation, Mechanisms of disease
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