The proximal tubular α7 nicotinic acetylcholine receptor attenuates ischemic acute kidney injury through Akt/PKC signaling-mediated HO-1 induction

• Published in: Experimental & molecular medicine Vol. 50; no. 4; pp. 1 - 17
• Main Authors: Kim, Hwajin, Kim, So Ra, Je, Jihyun, Jeong, Kyuho, Kim, Sooji, Kim, Hye Jung, Chang, Ki Churl, Park, Sang Won
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2018; Springer Nature B.V; Nature Publishing Group; 생화학분자생물학회
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/2; 13/89; 38; 45/77; 631/80/304; 64/60; 692/420/256/2516; 82; 82/51; 82/80; 96/95; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; AKT protein; alpha7 Nicotinic Acetylcholine Receptor - metabolism; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Caspase; Caspase-3; Cell activation; Cell death; Creatinine; Cytokines; DNA nucleotidylexotransferase; Gene expression; Gene Expression Regulation, Enzymologic; Heme; Heme oxygenase (decyclizing); Heme Oxygenase-1 - biosynthesis; HMGB1 protein; Inflammation; Ischemia; Ischemia - metabolism; Ischemia - pathology; Ischemia - prevention & control; Kidney Tubules, Proximal - blood supply; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - pathology; Kidneys; Kinases; Male; Medical Biochemistry; Membrane Proteins - biosynthesis; Metastases; Mice; Molecular Medicine; Molecular modelling; Oxygenase; Phenotypes; Protein kinase C; Protein Kinase C - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Proximal tubules; Reperfusion; Rodents; Signal Transduction; Stem Cells; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0061-x

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. Kidney injury: Nicotine and inflammation Nicotine may protect the kidney against ischemic reperfusion (IR) injury by reducing inflammation. IR injury is the tissue damage caused by a temporary block of blood flow leading to lack of oxygen and nutrient supply, followed by return of blood flow (reperfusion) resulting in excessive inflammation and oxidative stress. IR injury is the most common cause of acute kidney injury in hospitalized patients, sometimes leading to long-term kidney dysfunction. Sang Won Park and co-workers at the Gyeongsang National University School of Medicine, Jinju, South Korea investigated whether nicotinic receptor activation could reduce kidney injury in mice, using chemicals that stimulate or block the nicotine receptor. They found that stimulating the nicotine receptor decreased kidney inflammation and cell death through a kidney-specific molecular mechanism. These results may help treating kidney IR injury and long-term kidney dysfunction.