Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI

Xu, Xuan; Wang, Juan; Yang, Ruhao; Dong, Zheng; Zhang, Dongshan

doi:10.18632/oncotarget.21244

Cited by 18 publications

(22 citation statements)

References 44 publications

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“…CDDP: cisplatin; GL: Ganoderma lucidum; EOD: every other day; EGFR: epidermal growth factor receptor. 9 Oxidative Medicine and Cellular Longevity potential for AKI during endotoxemia and diabetic nephropathy [74,75]. Our results showed that the upregulation of EGFR, following CDDP injection, was significantly downregulated in rats treated with GL, and this correction was associated with the improvement that occurred in nephrotoxicity indices.…”

mentioning

confidence: 61%

“…EGFR may mediate renal injury by induction of inflammatory factors and cell apoptosis. However, inhibition of EGFR showed therapeutic potential for AKI during endotoxemia and diabetic nephropathy [ 74 , 75 ]. Our results showed that the upregulation of EGFR, following CDDP injection, was significantly downregulated in rats treated with GL, and this correction was associated with the improvement that occurred in nephrotoxicity indices.…”

Section: Discussionmentioning

confidence: 99%

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Ganoderma lucidum Prevents Cisplatin-Induced Nephrotoxicity through Inhibition of Epidermal Growth Factor Receptor Signaling and Autophagy-Mediated Apoptosis

Mahran

Hassan

2020

Oxidative Medicine and Cellular Longevity

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Background. Cisplatin (cis-diaminedichloroplatinum, CDDP) is a broad-spectrum antineoplastic agent. However, CDDP has been blamed for its nephrotoxicity, which is the main dose-limiting adverse effect. Ganoderma lucidum (GL), a medicinal mushroom, has antioxidant and inflammatory activities. Therefore, this study is aimed at finding out the potential nephroprotection of GL against CDDP-induced nephrotoxicity in rats and the possible molecular mechanisms including the EGFR downstream signaling, apoptosis, and autophagy. Methods. Rats were given GL (500 mg/kg) for 10 days and a single injection of CDDP (12 mg/kg, i.p). Results. Nephrotoxicity was evidenced by a significant increase in renal indices and oxidative stress markers. Additionally, CDDP showed a plethora of inflammatory and apoptotic responses as evidenced by a profound increase of HMGB-1, NF-κB, and caspase-3 expressions, whereas administration of GL significantly improved all these indices as well as the histopathological insults. Renal expression of EGFR showed a similar trend after GL administration. Furthermore, activation of autophagy protein, LC3 II, was found to be involved in GL-mediated nephroprotection correlated with the downregulation of apoptotic signaling, caspase-3 and terminal deoxynucleotidyl transferase (TDT) renal expressions. Conclusion. These results suggest that GL might have improved CDDP-induced nephrotoxicity through antioxidant, anti-inflammatory, and autophagy-mediated apoptosis mechanisms and that inhibition of EGFR signaling might be involved in nephroprotection.

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mentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Ganoderma lucidum Prevents Cisplatin-Induced Nephrotoxicity through Inhibition of Epidermal Growth Factor Receptor Signaling and Autophagy-Mediated Apoptosis

Mahran

Hassan

2020

Oxidative Medicine and Cellular Longevity

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“…The animal experiments were performed according to the rules approved by the animal ethics committee from Central South University. The HK-2 cells were as previously described (12,13).…”

Section: Van-induced Aki Modelmentioning

confidence: 99%

Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC‐δ

Pan

et al. 2018

FASEB j.

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Recent studies have shown that autophagy exhibits a renoprotective role in various models of acute kidney injury (AKI). However, its role in vancomycin (Van)‐induced AKI remains largely unclarified. This study was the first to indicate that autophagy was rapidly activated in both human kidney‐2 cells and renal tissues, and mammalian target of rapamycin (mTOR) was inactivated via the suppression of ERK1/2 and mTOR during Van treatment. Interestingly, for both in vitro and in vivo experiments, the suppression of autophagy via chloroquine and PT‐Atg7‐KO significantly ameliorated Van‐induced kidney injury and renal tubular cell apoptosis. Global gene expression analysis indicated that the expression levels of 6159 genes were induced by Van treatment in the kidney cortical tissues of PT‐Atg7 wild‐type mice, and 18 of them were notably suppressed in PT‐Atg7‐KO mice. These 18 genes were further classified as programmed cell death, protein binding, signal transduction, E3 ubiquitin ligase, nucleoside diphosphate kinase activity, and E1‐like activating enzyme. Unexpectedly, following Van treatment, PKC‐δ expression was found to be highest among the 4 genes related to cell death, which was remarkably suppressed in vitro and in PT‐Atg7‐KO mice. In addition, Atg7 could induce renal cell apoptosis during Van treatment via binding to PKC‐δ. Likewise, the inhibition of PKCδ ameliorated Van‐induced apoptosis in human kidney‐2 cells and kidney tissues. Furthermore, the data showed that PT‐Atg7‐KO exerted a renoprotective effect against Van‐induced nephrotoxicity, but this effect was lost after injection with myc‐tagged PKCδ. Taken altogether, these results indicate that Van induces autophagy by suppressing the activation of the ERK1/2 and mTOR signaling pathway. In addition, Atg7 mediates Van‐induced AKI through the activation of PKCδ. In sum, autophagy inhibition may serve as a novel therapeutic target for treating nephrotoxic AKI induced by Van.—Xu, X., Pan, J., Li, H., Li, X., Fang, F., Wu, D., Zhou, Y., Zheng, P., Xiong, L., Zhang, D. Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC‐δ. FASEB J. 33, 4513–4524 (2019). http://www.fasebj.org

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“…If the detailed information of our animal model is fully utilized and discussed, it will provide more basic data for future research. The existing research about the LPS concentrations in cell experiments ranges from 50 ng/ml to 10 μ g/ml [ 28 , 29 ] and the duration ranges from 30 minutes to 48 hours [ 29 , 30 ]. According to our experimental results, 30 μ g/ml LPS and culture duration of 6 h were selected for the cell model.…”

Section: Discussionmentioning

confidence: 99%

Role of Nrf2 in Lipopolysaccharide-Induced Acute Kidney Injury: Protection by Human Umbilical Cord Blood Mononuclear Cells

Feng

Zhao

Liu

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Acute kidney injury (AKI) is one of the common complications of sepsis. Heretofore, there is no effective treatment for septic AKI. Recent studies have revealed that besides treating hematological malignancies, human umbilical cord blood mononuclear cells (hUCBMNCs) show good therapeutic effects on other diseases. But whether hUCBMNCs can protect against septic AKI and its underlying mechanism are unknown. Methods. The rat model of lipopolysaccharide- (LPS-) induced AKI was developed, and the injection of hUCBMNCs was executed to prevent and treat AKI. ML385, a specific nuclear factor E2-related factor 2 (Nrf2) inhibitor, was used to silence Nrf2. The cell experiments were conducted to elaborate the protective mechanism of Nrf2 pathway. Results. An effective model of LPS-induced AKI was established. Compared to the rats only with LPS injection, the levels of inflammation, reactive oxygen species (ROS), and apoptosis in renal tissues after hUCBMNC injection were markedly attenuated. Pathological examination also indicated significant remission of renal tissue injury in the LPS+MNCs group, compared to rats in the LPS group. Transmission electron microscopy (TEM) showed that the damage of the mitochondria in the LPS+MNCs group was lighter than that in the LPS group. Noteworthily, the renal Nrf2/HO-1 pathway was activated and autophagy was enhanced after hUCBMNC injection. ML385 could partly reverse the renoprotective effect of hUCBMNCs, which could demonstrate that Nrf2 participated in the protection of hUCBMNCs. Cell experiments showed that increasing the expression level of Nrf2 could alleviate LPS-induced cell injury by increasing the autophagy level and decreasing the injury of the mitochondria in HK-2 cells. Conclusion. All results suggest that hUCBMNCs can protect against LPS-induced AKI via the Nrf2 pathway. Activating Nrf2 can upregulate autophagy to protect LPS-induced cell injury.

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Genetic or pharmacologic inhibition of EGFR ameliorates sepsis-induced AKI

Cited by 18 publications

References 44 publications

Ganoderma lucidum Prevents Cisplatin-Induced Nephrotoxicity through Inhibition of Epidermal Growth Factor Receptor Signaling and Autophagy-Mediated Apoptosis

Ganoderma lucidum Prevents Cisplatin-Induced Nephrotoxicity through Inhibition of Epidermal Growth Factor Receptor Signaling and Autophagy-Mediated Apoptosis

Atg7 mediates renal tubular cell apoptosis in vancomycin nephrotoxicity through activation of PKC‐δ

Role of Nrf2 in Lipopolysaccharide-Induced Acute Kidney Injury: Protection by Human Umbilical Cord Blood Mononuclear Cells

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