Augmented O-GlcNAc signaling via glucosamine attenuates oxidative stress and apoptosis following contrast-induced acute kidney injury in rats

Hu, Jiayue; Chen, Rongyi; Jia, Ping; Fang, Yi; Liu, Tongqiang; Song, Ning; Xu, Xiaowu; Ji, Jun; Ding, Xiaoqiang

doi:10.1016/j.freeradbiomed.2016.12.032

Cited by 48 publications

(46 citation statements)

References 52 publications

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“…These findings suggest that aging is associated with a decline in the capacity of cells to activate these posttranslational modifications, particularly SUMOylation and O‐GlcNAcylation. Rapid activation of both modifications has been reported in various postischemic organs 6, 8, 27, 28, 29, 30. Notably, in the present study, these were the only posttranslational modifications that showed impaired activation in both brain and kidney of aged mice.…”

Section: Discussionsupporting

confidence: 66%

“…Recently, we reported that aging is associated with impaired activation of O‐GlcNAcylation in the stroke penumbra and worse outcome, and that pharmacologic activation of O‐GlcNAcylation improves stroke outcome 8. Considering that increased O‐GlcNAcylation is neuroprotective,8 cardioprotective,29 and renoprotective,30 pharmacologic boosting of O‐GlcNAcylation is expected to protect a variety of organs exposed to I/R injury, which would be particularly beneficial in CA/CPR that causes whole‐body I/R injury. Indeed, our data showed that posttreatment with thiamet‐G improved functional outcome and reduced CA1 neuronal death after CA/CPR (Figure 9).…”

Section: Discussionmentioning

confidence: 99%

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Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Shen

Yan

Zhao

et al. 2018

JAHA

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BackgroundThe mechanisms underlying worse outcome at advanced age after cardiac arrest (CA) and resuscitation are not well understood. Because protein homeostasis (proteostasis) is essential for cellular and organismal health, but is impaired after CA, we investigated the effects of age on proteostasis‐related prosurvival pathways activated after CA.Methods and ResultsYoung (2–3 months old) and aged (21–22 months old) male C57Bl/6 mice were subjected to CA and cardiopulmonary resuscitation (CPR). Functional outcome and organ damage were evaluated by assessing neurologic deficits, histological features, and creatinine level. CA/CPR‐related changes in small ubiquitin‐like modifier conjugation, ubiquitination, and the unfolded protein response were analyzed by measuring mRNA and protein levels in the brain, kidney, and spinal cord. Thiamet‐G was used to increase O‐linked β‐N‐acetylglucosamine modification. After CA/CPR, aged mice had trended lower survival rates, more severe tissue damage in the brain and kidney, and poorer recovery of neurologic function compared with young mice. Furthermore, small ubiquitin‐like modifier conjugation, ubiquitination, unfolded protein response, and O‐linked β‐N‐acetylglucosamine modification were activated after CA/CPR in young mice, but their activation was impaired in aged mice. Finally, pharmacologically increasing O‐linked β‐N‐acetylglucosamine modification after CA improved outcome.ConclusionsResults suggest that impaired activation of prosurvival pathways contributes to worse outcome after CA/CPR in aged mice because restoration of proteostasis is critical to the survival of cells stressed by ischemia. Therefore, a pharmacologic intervention that targets aging‐related impairment of proteostasis‐related pathways after CA/CPR may represent a promising therapeutic strategy.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Shen

Yan

Zhao

et al. 2018

JAHA

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“…Akt activation phosphorylates and inactivates several apoptosis-inducing factors, including Bax [10]. The phosphorylation of Akt (Ser 473 ) and eNOS (Ser 1177 ) upregulates the anti-apoptotic Bcl-2 family proteins and switches-off caspase-3 activity via S-nitrosylation of its active center p17 [8, 9]. Meanwhile, activation of PI3K/Akt pathway plays a critical role in modulating Nrf2-dependent attenuation of oxidative stress [8].…”

Section: Discussionmentioning

confidence: 99%

“…The phosphorylation of Akt (Ser 473 ) and eNOS (Ser 1177 ) upregulates the anti-apoptotic Bcl-2 family proteins and switches-off caspase-3 activity via S-nitrosylation of its active center p17 [8, 9]. Meanwhile, activation of PI3K/Akt pathway plays a critical role in modulating Nrf2-dependent attenuation of oxidative stress [8]. In the current study, 5-FU suppressed the PI3K/Akt/eNOS pathway with consequent decline of NO levels.…”

Section: Discussionmentioning

confidence: 99%

“…An intimate pathway linked to the apoptotic cell death is the phosphoinositide-3-kinase/ protein kinase B (PI3K/Akt) pathway which can be modulated by several renal toxicants. PI3K/Akt has been reported to control cellular survival signals via interaction with the Bcl-2 family [8, 9]. Akt has also been linked to renal NO production through activation of the endothelial nitric oxide synthase (eNOS) [10].…”

Section: Introductionmentioning

confidence: 99%

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Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

Arab

Salama

Maghrabi

2018

Cell Physiol Biochem

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Background/Aims: The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats. Methods: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting. Results: CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use. Conclusion: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K/Akt/eNOS pathway.

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An in vivo and in vitro model on the protective effect of cilnidipine on contrast‐induced nephropathy via regulation of apoptosis and CaMKⅡ/mPTP pathway

Liu

Zhou

et al. 2022

J Biochem & Molecular Tox

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Contrast‐induced nephropathy (CIN) is an acute kidney injury (AKI) observed after the administration of contrast media. Calcium channel blockers (CCBs) have been reported to exert a renal protective effect. This study aims to investigate the role of cilnidipine, a novel CCBs, on CIN by regulating the calcium/calmodulin‐dependent protein kinase Ⅱ(CaMKⅡ)/mitochondrial permeability transition pore (mPTP) pathway. Here, iohexol, a representative contrast media, was used to establish CIN model. KN‐93 (CaMKⅡ inhibitor) and atractyloside (mPTP opener) were administered in rats, and CaMKⅡ overexpression was used in Human proximal tubular epithelial cells. Markers of renal injury (serum creatinine, blood urea nitrogen, and urinary NAGL), hematoxylin‐eosin stain, oxidative stress (ROS, superoxide dismutase [SOD], and malondialdehyde [MDA] levels), cell death (MTT and terminal deoxynucleotidyl transferase‐mediated deoxyuridine triphosphate nick end labeling [TUNEL]), mitochondrial function (mPTP, mitochondrial membrane potential [MMP], and ATP) were assessed. Western blots were used to measure the expression levels of Bax/Bcl‐2, caspase‐3, CaMKⅡ/mPTP signaling pathways. Results showed that cilnidipine markedly improved kidney function, and alleviated tubular cell apoptosis, oxidative stress and mitochondrial damage induced by iohexol in vitro and in vivo. The underlying mechanism may be that cilnidipine relieved CaMKⅡ activation and mPTP opening induced by iohexol. All of these protective effects of cilnidipine were attenuated by CaMKⅡ overexpression and atractyloside (mPTP opener) pretreatment. Moreover, KN‐93 (CaMKⅡ inhibitor) treatment showed a similar renal protective effect with cilnidipine, while the protective effect of cilnidipine on kidney in CIN rats was not further suppressed by KN‐93 cotreatment. These in vitro and in vivo results point toward the fact that cilnidipine might be a novel therapeutic drug against contrast‐induced nephrotoxicity in a CaMKⅡ‐dependent manner.

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Augmented O-GlcNAc signaling via glucosamine attenuates oxidative stress and apoptosis following contrast-induced acute kidney injury in rats

Cited by 48 publications

References 52 publications

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Aging Is Associated With Impaired Activation of Protein Homeostasis‐Related Pathways After Cardiac Arrest in Mice

Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-κB and PI3K/Akt/eNOS Pathways

An in vivo and in vitro model on the protective effect of cilnidipine on contrast‐induced nephropathy via regulation of apoptosis and CaMKⅡ/mPTP pathway

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