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Published on: July 17, 2016
Xenon Protects Against Septic Acute Kidney Injury via miR-21 Target Signaling Pathway
Ping Jia1, Jie Teng, Jianzhou Zou
11Division of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, China. 2Kidney and Dialysis Institute of Shanghai, Shanghai, China. 3Kidney and Blood Purification Laboratory of Shanghai, Shanghai, China. 4Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
Objectives:
Septic acute kidney injury is one of the most common and life-threatening complications in critically ill patients, and there is no approved effective treatment. We have shown xenon provides renoprotection against ischemia-reperfusion injury and nephrotoxicity in rodents via inhibiting apoptosis. Here, we studied the effects of xenon preconditioning on septic acute kidney injury and its mechanism.
Design:
Experimental animal investigation.
Setting:
University research laboratory.
Subjects:
Experiments were performed with male C57BL/6 mice, 10 weeks of age, weighing 20-25 g.
Interventions:
We induced septic acute kidney injury by a single intraperitoneal injection of Escherichia coli lipopolysaccharide at a dose of 20 mg/kg. Mice were exposed for 2 hours to either 70% xenon or 70% nitrogen, 24 hours before the onset of septic acute kidney injury. In vivo knockdown of miR-21 was performed using locked nucleic acid-modified anti-miR, the role of miR-21 in renal protection conferred by the xenon preconditioning was examined, and miR-21 signaling pathways were analyzed.
Measurements And Main Results:
Xenon preconditioning provided morphologic and functional renoprotection, characterized by attenuation of renal tubular damage, apoptosis, and a reduction in inflammation. Furthermore, xenon treatment significantly upregulated the expression of miR-21 in kidney, suppressed proinflammatory factor programmed cell death protein 4 expression and nuclear factor-κB activity, and increased interleukin-10 production. Meanwhile, xenon preconditioning also suppressed the expression of proapoptotic protein phosphatase and tensin homolog deleted on chromosome 10, activating protein kinase B signaling pathway, subsequently increasing the expression of antiapoptotic B-cell lymphoma-2, and inhibiting caspase-3 activity. Knockdown of miR-21 upregulated its target effectors programmed cell death protein 4 and phosphatase and tensin homolog deleted on chromosome 10 expression, resulted in an increase in apoptosis, and exacerbated lipopolysaccharide-induced acute kidney injury.
Conclusion:
Our findings demonstrated that xenon preconditioning protected against lipopolysaccharide-induced acute kidney injury via activation of miR-21 target signaling pathways.
Insights
Xenon preconditioning protects against septic acute kidney injury by upregulating miR-21, reducing inflammation and apoptosis. This study reveals xenon’s potential therapeutic mechanism for kidney injury.
Area of Science:
- Nephrology
- Critical Care Medicine
- Anesthesiology
Background:
- Septic acute kidney injury (AKI) is a severe complication in critically ill patients with no effective treatment.
- Xenon has demonstrated renoprotective effects against injury and nephrotoxicity by inhibiting apoptosis.
Purpose of the Study:
- To investigate the protective effects of xenon preconditioning on septic AKI.
- To elucidate the underlying mechanisms of xenon's renoprotection, focusing on miR-21 signaling.
Main Methods:
- Male C57BL/6 mice underwent septic AKI induction via lipopolysaccharide (LPS) injection.
- Mice were preconditioned with xenon or nitrogen 24 hours prior to LPS exposure.
- miR-21 expression and its downstream signaling pathways were analyzed, including in vivo knockdown studies.
Main Results:
- Xenon preconditioning attenuated renal tubular damage, apoptosis, and inflammation in septic AKI.
- Xenon upregulated kidney miR-21, suppressed inflammation (via PDCD4, NF-κB), and increased IL-10.
- Xenon also modulated apoptosis-related proteins (PTEN, Akt, Bcl-2, caspase-3) and miR-21 knockdown reversed these protective effects.
Conclusions:
- Xenon preconditioning offers significant protection against LPS-induced septic AKI.
- The renoprotective effects are mediated through the activation of miR-21 target signaling pathways.
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