Relaxin attenuates aristolochic acid induced human tubular epithelial cell apoptosis in vitro by activation of the PI3K/Akt signaling pathway

Xie, Xiangcheng; Zhao, Ning; Xu, Qunhong; Yang, Xiu Hong; Xia, Wenqing; Chen, Qi; Wang, Ming; Xiao, Fei

doi:10.1007/s10495-017-1369-z

Cited by 20 publications

(8 citation statements)

References 35 publications

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“…It has been demonstrated that renal tubular epithelial cell is the main target of AAAs, and AAN is characterized by excessive death of renal tubular epithelial cells (Zhou et al, 2010;Huang et al, 2013). For the past few years, several cell death modes, including apoptosis, necrosis, and autophagy, have been proved to be responsible for AA-induced cell death (Zhou et al, 2010;Baudoux et al, 2012;Zeng et al, 2014;Xie et al, 2017;Yang et al, 2019). While ferroptosis, a new form of regulated cell death, has been reported to be related to various diseases, including kidney injury.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Deng¹,

Yue²,

Wang

et al. 2021

Front. Pharmacol.

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Aristolactam I (ALI) is an active component derived from some Traditional Chinese medicines (TCMs), and also the important metabolite of aristolochic acid. Long-term administration of medicine-containing ALI was reported to be related to aristolochic acid nephropathy (AAN), which was attributed to ALI-induced nephrotoxicity. However, the toxic mechanism of action involved is still unclear. Recently, pathogenic ferroptosis mediated lipid peroxidation was demonstrated to cause kidney injury. Therefore, this study explored the role of ferroptosis induced by mitochondrial iron overload in ALI-induced nephrotoxicity, aiming to identify the possible toxic mechanism of ALI-induced chronic nephropathy. Our results showed that ALI inhibited HK-2 cell activity in a dose-dependent manner and significantly suppressed glutathione (GSH) levels, accompanying by significant increases in intracellular 4-hydroxynonenal (4-HNE) and intracellular iron ions. Moreover, the ALI-mediated cytotoxicity could be reversed by deferoxamine mesylate (DFO). Compared with other inhibitors, Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, obviously alleviated ALI-induced cytotoxicity. Furthermore, we have shown that ALI could remarkably increase the levels of superoxide anion and ferrous ions in mitochondria, and induce mitochondrial damage and condensed mitochondrial membrane density, the morphological characteristics of ferroptosis, all of which could be reversed by DFO. Interestingly, ALI dose-dependently inhibited these protein contents of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4), which could be partly rescued by Tin-protoporphyrin IX (SnPP) and mitoTEMPO co-treatment. In conclusion, our results demonstrated that mitochondrial iron overload-mediated antioxidant system inhibition would assist ALI-induced ferroptosis in renal tubular epithelial cells, and Nrf2-HO-1/GPX4 antioxidative system could be an important intervention target to prevent medicine containing ALI-induced nephropathy.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Deng¹,

Yue²,

Wang

et al. 2021

Front. Pharmacol.

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“…Moreover, the increased levels of p85 upon cellular stimulation correlates with sustained AKT phosphorylation in cells (Esposito et al, 2008). Recent reports showed that the PI3K/AKT/GSK-3β pathway has been reported involved in cell proliferation (Chan et al, 2018), apoptosis (Xie et al, 2017), and inflammation (Jing et al, 2017) in various kidney diseases. Currently accumulating evidence supports that the PI3K/AKT signaling pathway contributes to the promotion of proliferation in mesangial cells (Feng et al, 2016; Ying et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Paeoniflorin Inhibits Mesangial Cell Proliferation and Inflammatory Response in Rats With Mesangial Proliferative Glomerulonephritis Through PI3K/AKT/GSK-3β Pathway

et al. 2019

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Mesangial proliferative glomerulonephritis (MPGN) is the most common type of chronic kidney disease in China, characterized by mesangial cell proliferation and inflammatory response. Paeoniflorin, an effective composition extracted from Radix Paeoniae Alba, has been used for various kinds of kidney diseases. However, there are no studies reporting the effects of paeoniflorin on MPGN. The present study aims to investigate whether paeoniflorin plays a role in MPGN and confirm the underlying molecular mechanisms. Our results manifested that paeoniflorin strongly restrained 24 h urinary protein and promoted renal function and dyslipidemia in a MPGN rat model. Moreover, paeoniflorin attenuated mesangial cell proliferation and inflammation both in MPGN rats and human mesangial cells (HMCs) treated with lipopolysaccharide (LPS). In detail, paeoniflorin decreased the number of mesangial cells and expressions of proliferation marker Ki67 in MPGN rats. Paeoniflorin also inhibited HMC proliferation and blocked cell cycle progression. In addition, the contents of inflammatory factors and the expressions of macrophage marker iNOS were decreased after paeoniflorin treatment. Furthermore, we found that the protective effect of paeoniflorin was accompanied by a strong inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT/glycogen synthase kinase (GSK)-3β pathway. Paeoniflorin enhanced the inhibitory effect of PI3K inhibitor LY294002 and suppressed the activated effect of PI3K agonist insulin-like growth factor 1 (IGF-1) on PI3K/AKT/GSK-3β pathway. In conclusion, these results demonstrated that paeoniflorin ameliorates MPGN by inhibiting mesangial cell proliferation and inflammatory response through the PI3K/AKT/GSK-3β pathway.

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“…Chen et.al showed that the protection of renal injury in diabetic rats is related to the inhibition of the PI3K/AKT pathway (Chen et al, 2017 ). However, the studies with Xie (Xie et al, 2017 ) and Kalmar-Nagy (Kalmar-Nagy et al, 2013 ) have shown that alleviating renal injury is associated with activation of the AKT signaling pathway. So the role of AKT signaling pathway is controversial in the current research.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Curcumin Renoprotection in Experimental Acute Renal Injury

et al. 2017

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As a highly perfused organ, the kidney is especially sensitive to ischemia and reperfusion. Ischemia-reperfusion (IR)-induced acute kidney injury (AKI) has a high incidence during the perioperative period in the clinic and is an important link in ischemic acute renal failure (IARF). Therefore, IR-induced AKI has important clinical significance and it is necessary to explore to develop drugs to prevent and alleviate IR-induced AKI. Curcumin [diferuloylmethane, 1,7-bis(4-hydroxy-3-methoxiphenyl)-1,6-heptadiene-3,5-dione)] is a polyphenol compound derived from Curcuma longa (turmeric) and was shown to have a renoprotective effect on ischemia-reperfusion injury (IRI) in a previous study. However, the specific mechanisms underlying the protective role of curcumin in IR-induced AKI are not completely understood. APPL1 is a protein coding gene that has been shown to be involved in the crosstalk between the adiponectin-signaling and insulin-signaling pathways. In the study, to investigate the molecular mechanisms of curcumin effects in kidney ischemia/reperfusion model, we observed the effect of curcumin in experimental models of IR-induced AKI and we found that curcumin treatment significantly increased the expression of APPL1 and inhibited the activation of Akt after IR treatment in the kidney. Our in vitro results showed that apoptosis of renal tubular epithelial cells was exacerbated with hypoxia-reoxygenation (HR) treatment compared to sham control cells. Curcumin significantly decreased the rate of apoptosis in renal tubular epithelial cells with HR treatment. Moreover, knockdown of APPL1 activated Akt and subsequently aggravated apoptosis in HR-treated renal tubular epithelial cells. Conversely, inhibition of Akt directly reversed the effects of APPL1 knockdown. In summary, our study demonstrated that curcumin mediated upregulation of APPL1 protects against ischemia reperfusion induced AKI by inhibiting Akt phosphorylation.

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Relaxin attenuates aristolochic acid induced human tubular epithelial cell apoptosis in vitro by activation of the PI3K/Akt signaling pathway

Cited by 20 publications

References 35 publications

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Mitochondrial Iron Overload-Mediated Inhibition of Nrf2-HO-1/GPX4 Assisted ALI-Induced Nephrotoxicity

Paeoniflorin Inhibits Mesangial Cell Proliferation and Inflammatory Response in Rats With Mesangial Proliferative Glomerulonephritis Through PI3K/AKT/GSK-3β Pathway

Molecular Mechanisms of Curcumin Renoprotection in Experimental Acute Renal Injury

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