Dexmedetomidine attenuates lung apoptosis induced by renal ischemia–reperfusion injury through α2AR/PI3K/Akt pathway

Abstract

BackgroundAcute lung injury caused by renal ischemia–reperfusion is one of the leading causes of acute kidney injury-related death. Dexmedetomidine, an α2-adrenergic agonist sedative, has been found to have protective effects against acute kidney injury and remote lung injury. We sought to determine whether dexmedetomidine can exert its anti-apoptotic effects in acute lung injury after acute kidney injury, in addition to its common anti-inflammatory effects, and to determine the underlying mechanisms.MethodsIn vivo, acute kidney injury was induced by 60 min of kidney ischemia (bilateral occlusion of renal pedicles) followed by 24 h of reperfusion. Mice received dexmedetomidine (25 µg/kg, i.p.) in the absence or presence of α2-adrenergic antagonist atipamezole (250 µg/kg, i.p.) before IR. Histological assessment of the lung was conducted by HE staining and arterial blood gases were measured. Lung apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay. The expression of caspase 3 and p-Akt in lung tissue was detected by western blot. In vitro, C57BL/6J mice pulmonary microvascular endothelial cells were treated with serum from mice obtained following sham or IR. Dexmedetomidine was given before serum stimulation in cells, alone or with atipamezole or LY294002. Cell viability was assessed by CCK 8 assay. Cell apoptosis was examined by Hoechst staining and Annexin V-FITC/PI staining flow cytometry analysis. Mitochondrial membrane potential was measured by flow cytometry. The expression of p-Akt, caspase 3, Bcl-2 and Bax was measured by western blot.ResultsIn vivo, dexmedetomidine remarkably mitigated pathohistological changes and apoptosis and significantly increased p-Akt expression in the lung. In addition, dexmedetomidine also slightly improved oxygenation in mice after IR, which can be abolished by atipamezole. In vitro, dexmedetomidine significantly inhibited IR serum-induced loss of viability and apoptosis in PMVECs. Dexmedetomidine increased p-Akt in a time- and dose-dependent manner, and down-regulated the expression of caspase 3 and Bax and up-regulated the Bcl-2 expression in PMVECs. The changes of MMP were also improved by dexmedetomidine. Whilst these effects were abolished by Atipamezole or LY294002.ConclusionOur results demonstrated that dexmedetomidine attenuates lung apoptosis induced by IR, at least in part, via α2AR/PI3K/Akt pathway.

Tanshinone IIA Combined With CsA Inhibit Myocardial Cell Apoptosis Induced by Renal Ischemia-reperfusion Injury by Modulating Mitochondrial Function Through PI3K/Akt/Bad Pathway in Obese Rats 

“…However, TIIA, CsA, or TIIA+CsA decreased caspase-9/3 activity in myocardial cells ( Figure 3B, C). These results are similar to those of Juanjuan Liet al [38]. in an acute lung injury model induced by renal IRI.…”

“…According to previous studies, some anti-in ammatory agents have been discovered, including αmelanocyte stimulating hormone, anti-apoptotic agents, and IL-6 inhibitors [38,39]. A previous study reported that renal IR induces dysfunction in lung mitochondria and dexmedetomidine attenuates lung in ammation, apoptosis, and the MMP [38]. However, until now, no study has investigated myocardial mitochondrial dysfunction induced by renal IR, and no anti-mitochondrial dysfunction agents have been discovered to protect against AMI induced by renal IR in obese rats.…”

Pretreatment with dexmedetomidine alleviates lung injury in a rat model of intestinal ischemia reperfusion

“…Via α2-adrenergic receptors, deX has demonstrated sedative, analgesic, anti-anxiety and diuresis effects (40,41). in addition, the anti-apoptosis effect of deX was inhibited by the α2-adrenoceptor antagonist aTi in liver ischemia-reperfusion injury and renal ischemia-reperfusion injury (10,18). The present study further demonstrated that the antioxidant and anti-inflammatory action of DEX in lung injury during IIR was also acting on the α2-adrenoceptor.…”

“…experiment 1 was designed to test the effects of deX (Jiangsu Hengrui Medicine co., ltd., Jiangsu, china) pretreatment on pathological damage to the lung during iir and to select the optimal drug dose. at present, the majority of researchers have selected 25-50 µg/kg deX (injected intraperitoneally) in order to study its protection against ischemia reperfusion injury (18)(19)(20). intravenous injection of deX always requires small doses ranging from 1 to 10 µg/kg (21,22).…”

Dexmedetomidine post‐treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF‐1α signalling

“…[11][12][13] In addition to its cardioprotective benefits, DEX has been found to attenuate I/R injury in other vital organs, including the brain, liver, kidney, lungs and spinal cord. [34][35][36][37][38] Few studies have investigated the effects of DEX post-treatment; however, administration at the onset of reperfusion is more applicable in clinical practice. A previous study failed to show the protective effect of DEX post-treatment against myocardial injury.…”