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      Ozone oxidative postconditioning inhibits oxidative stress and apoptosis in renal ischemia and reperfusion injury through inhibition of MAPK signaling pathway

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          Ozone has been used as a curative agent for a variety of different diseases for over 150 years. In our previous study, we found that ozone oxidative preconditioning could alleviate renal damage induced by ischemia and reperfusion injury (I/R). Although this method had obvious protective effects in the reduction of I/R, its clinical application remains limited because this treatment must be commenced prior to the ischemic period, which is not practical in the clinic.


          In the present study, we investigated whether ozone oxidative postconditioning (OzoneOP) could attenuate renal I/R in vivo and in vitro, as well as the mechanisms underlying the effects of this treatment.


          Sprague Dawley rats were subjected to right renal ischemia for 45 min and reperfusion for 24 h, or to sham operation with the left kidney removed, both with and without OzoneOP. In addition, normal rat kidney tubular epithelial cells (NRK-52E) were chosen to create a hypoxia–reoxygenation (H/R) model of 3 h hypoxia and 24 h reoxygenation processes, both with or without OzoneOP and mitogen-activated protein kinase (MAPK) inhibitors.


          Our results showed that OzoneOP significantly reversed apoptosis and the abnormal superoxide dismutase and malondialdehyde levels induced by I/R or H/R. OzoneOP also inhibited activation of the MAPK pathways both in vivo and in vitro, which resulted in significant protection against apoptosis and oxidative stress.


          Our current data provide evidence that OzoneOP might serve as a potential therapy for renal I/R.

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          Most cited references 21

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          Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms.

          A mechanism by which the Ras-mitogen-activated protein kinase (MAPK) signaling pathway mediates growth factor-dependent cell survival was characterized. The MAPK-activated kinases, the Rsks, catalyzed the phosphorylation of the pro-apoptotic protein BAD at serine 112 both in vitro and in vivo. The Rsk-induced phosphorylation of BAD at serine 112 suppressed BAD-mediated apoptosis in neurons. Rsks also are known to phosphorylate the transcription factor CREB (cAMP response element-binding protein) at serine 133. Activated CREB promoted cell survival, and inhibition of CREB phosphorylation at serine 133 triggered apoptosis. These findings suggest that the MAPK signaling pathway promotes cell survival by a dual mechanism comprising the posttranslational modification and inactivation of a component of the cell death machinery and the increased transcription of pro-survival genes.
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            Apoptosis and acute kidney injury.

            Improved mechanistic understanding of renal cell death in acute kidney injury (AKI) has generated new therapeutic targets. Clearly, the classic lesion of acute tubular necrosis is not adequate to describe the consequences of renal ischemia, nephrotoxin exposure, or sepsis on glomerular filtration rate. Experimental evidence supports a pathogenic role for apoptosis in AKI. Interestingly, proximal tubule epithelial cells are highly susceptible to apoptosis, and injury at this site contributes to organ failure. During apoptosis, well-orchestrated events converge at the mitochondrion, the organelle that integrates life and death signals generated by the BCL2 (B-cell lymphoma 2) protein family. Death requires the 'perfect storm' for outer mitochondrial membrane injury to release its cellular 'executioners'. The complexity of this process affords new targets for effective interventions, both before and after renal insults. Inhibiting apoptosis appears to be critical, because circulating factors released by the injured kidney induce apoptosis and inflammation in distant organs including the heart, lung, liver, and brain, potentially contributing to the high morbidity and mortality associated with AKI. Manipulation of known stress kinases upstream of mitochondrial injury, induction of endogenous, anti-apoptotic proteins, and improved understanding of the timing and consequences of renal cell apoptosis will inevitably improve the outcome of human AKI.
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              An experimental model for assessment of renal recovery from warm ischemia.

              A study was made of the acute and chronic (15 days) functional and morphologic effects on the rat kidney of warm ischemia and contralateral nephrectomy, in order to define a suitable animal model for testing renal transplant preservation techniques when warm ischemia is a contributing factor. Spontaneous recovery from 30-min warm ischemia was complete, and the model was consequently unsuitable; the high mortality from 90 min was unacceptable. Warm ischemia of 60 minutes produced severe renal tubular necrosis, an acceptable mortality, residual morphologic damage, and impairment of isolated kidney perfusion parameters at 15 days. Renal function in vivo was normal in many of these animals, despite appreciable residual morphologic changes, and it is evident that functional data alone are not sufficient for assessment of preservation regimens.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                21 May 2018
                : 12
                : 1293-1301
                Department of Urology, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China
                Author notes
                Correspondence: Zhiyuan Chen, Department of Urology, Renmin Hospital of Wuhan University, No 238 Jiefang Road, Wuhan 430060, Hubei Province, P. R. China, Tel +86 278 804 1911, Fax +86 278 804 1911, Email chenzhiyuan163@ 123456163.com
                © 2018 Wang et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Original Research

                Pharmacology & Pharmaceutical medicine

                ozone, ischemia and reperfusion, mapk


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