Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Targeted depletion of renal ALKBH7 by bismuth drug prevents cisplatin-induced acute kidney injury

ABSTRACT: Cisplatin is a potent chemotherapeutic drug widely used to treat cancers. Unfortunately, its overaccumulation in kidney proximal tubular cell (PTC) shuts down fatty acid oxidation, resulting in cell necrosis and acute kidney injury (AKI). Bismuth drugs have long been used to treat gastrointestinal tract disorder and Helicobacter pylori infection. Interestingly, bismuth drugs also mitigate cisplatin-induced AKI, but the underlying mechanism remains unknown. In this study, we found 50nM bismuth specifically reduces cisplatin-induced cell necrosis. Using multiomics and protein-small molecule interaction techniques, we identified mitochondrial protein ALKBH7 as a specific target of bismuth. And ALKBH7 is depleted upon bismuth treatment. Bismuth treatment and ALKBH7 knockdown shared a proteomic similarity in suppressing programmed necrosis and promoting fatty acid metabolism. By gene knockout and silencing, we showed ALKBH7 depletion indeed greatly mitigates cisplatin-induced cell necrosis. We further demonstrated bismuth specifically depletes renal ALKBH7, prevents cisplatin-induced AKI and greatly increases survival rate in mice. Overall, we conclude ALKBH7 is specific target of bismuth drugs, and ALKBH7 depletion suppresses cisplatin-induced PTC necrosis and prevents AKI by preserving fatty acid metabolism.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Yifan Hong

PROVIDER: PXD054362 | iProX | Tue Jul 30 00:00:00 BST 2024

REPOSITORIES: iProX

ACCESS DATA

Json Xml

Similar Datasets

Yishen Jiangzhuo decoction attenuates cisplatin-induced acute kidney injury by inhibiting inflammation, oxidative stress, and apoptosis through the TNF signal pathway

Project description:We aimed to investigate the therapeutic effects and mechanisms of Yishen Jiangzhuo decoction (YSJZD) in a mouse model of cisplatin-induced acute kidney injury (AKI). The mice were divided into the NC, cisplatin, and cisplatin + YSJZD groups. A concentration-dependent effect of YSJZD on cisplatin-induced AKI was observed, and the optimal concentration for intervention was calculated. Changes in blood urea nitrogen and serum creatinine levels combined with hematoxylin & eosin and periodic acid-Schiff staining, and transmission electron microscopy observations indicated that YSJZD enhanced renal function, reduced pathological injury, and protected renal tubular epithelial cells in cisplatin-induced AKI mice. The results of the transcriptomic and enrichment analyses showed that the mechanisms of YSJZD may be associated with inflammation, oxidation, apoptosis, and the TNF signal pathway. Immunofluorescence, oxidative stress index, terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and western blotting (WB) revealed that YSJZD downregulated apoptosis in the renal tissues of AKI mice, and further decreased the expression levels of p-p65, p-p38 MAPK, tumor necrosis factor -α, cleaved-caspase-3, and malondialdehyde, while increasing the levels of SIRT3, GSH, and SOD. Overall, the results showed that YSJZD could effectively abrogate cisplatin-induced AKI in mice through mechanisms primarily related to its anti-inflammatory, antioxidative, and antiapoptotic effects by inhibited the TNF signal pathway. YSJZD warrants further investigation as a clinical empirical prescription.

2024-04-06 | GSE262792 | GEO

Identification and Validation of Hub Genes in Drug Induced Acute Kidney Injury Basing on Integrated Transcriptomic Analysis

Project description:In this study, RNA-seq was used to detect mRNA changes in DI-AKI cell models induced by three drugs (Iohexol, cisplatin and vancomycin), and was analyzed and validated to screen key hub genes and specific biomarkers for DI-AKI.

2023-03-27 | GSE227970 | GEO

Proteomic analysis of cisplatin exposure on the kidney cortex proteome and the effect of preconditioning

Project description:Acute kidney injury and nephrotoxicity are important clinical side effects of cisplatin. Thus, the mechanisms of this disease, and potential treatment options are important to understand in their entity. Here, we analyzed the proteome of cisplatin induced acute kidney injury in a mouse model. Functionally we found that calorie restriction was able to completely blunt Cisplatin induced AKI, and hypoxia ameliorated cCisplatin induced AKI. To investigate the mechanism for this in high throughput, we performed label-free single-shot proteomic analyses of these kidneys.Acute kidney injury and nephrotoxicity are important clinical side effects of cisplatin. Thus, the mechanisms of this disease, and potential treatment options are important to understand in their entity. Here, we analyzed the proteome of cisplatin induced acute kidney injury in a mouse model. Functionally we found that calorie restriction was able to completely blunt Cisplatin induced AKI, and hypoxia ameliorated cCisplatin induced AKI. To investigate the mechanism for this in high throughput, we performed label-free single-shot proteomic analyses of these kidneys.

2020-01-30 | PXD005525 | Pride

Evaluation of cisplatin-induced injury in human kidney organoids

Project description:Acute kidney injury (AKI) remains a major global healthcare problem and there is a need to develop human-based models to study AKI in vitro. Towards this goal, we have characterized induced pluripotent stem cell-derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 µM cisplatin induces HAVCR1 and CXCL8 expression, DNA damage (γH2AX) and cell death in the organoids in a dose-dependent manner but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of the proximal tubule-specific SLC22A2/OCT2 transporter for cisplatin. To improve viability, we developed a repeated low-dose regimen of 4x 5 µM cisplatin over 7 days and found this causing less toxicity while still inducing a robust AKI response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of AKI, with the potential to identify new AKI biomarkers and develop better therapies.

2020-02-29 | GSE145085 | GEO

Inhibition of Collagen XI alpha 1–induced Fatty Acid Oxidation Triggers Apoptotic Cell Death in Cisplatin-Resistant Ovarian Cancer

Project description:Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. However, the mechanisms underlying how COL11A1 confers cisplatin resistance in ovarian cancer are poorly understood. We identified that fatty acid β-oxidation (FAO) is upregulated by COL11A1 in ovarian cancer cells and that COL11A1-driven cisplatin resistance can be abrogated by inhibition of FAO. Furthermore, our results demonstrate that COL11A1 also enhances the expression of proteins involved in fatty acid synthesis. Interestingly, COL11A1-induced upregulation of fatty acid synthesis and FAO is modulated by the same signaling molecules. We identified that binding of COL11A1 to its receptors, α1β1 integrin and discoidin domain receptor 2 (DDR2), activates Src-Akt-AMPK signaling to increase the expression of both fatty acid synthesis and oxidation enzymes, although DDR2 seems to be the predominant receptor. Inhibition of fatty acid synthesis downregulates FAO despite the presence of COL11A1, suggesting that fatty acid synthesis might be a driver of FAO in ovarian cancer cells. Taken together, our results suggest that COL11A1 upregulates fatty acid metabolism in ovarian cancer cells in a DDR2-Src-Akt-AMPK dependent manner. Therefore, we propose that blocking FAO might serve as a promising therapeutic target to treat ovarian cancer, particularly cisplatin-resistant recurrent ovarian cancers which typically express high levels of COL11A1.

2020-04-28 | PXD016244 | Pride

FXR protects cisplatin-induced AKI via transcriptional regulation of ferroptosis.

Project description:Farnesoid X receptor (FXR, also known as NR1H4) is crucial to nephroprotective in several kinds of kidney diseases, including obesity, diabetes, aging, acute kidney injury and chronic kidney disease. FXR plays a key role in maintaining cholesterol and bile acid levels and is highly expressed in the liver, intestine and kidneys. In kidney diseases, it is reported that FXR has anti-lipogenic, anti‐inflammatory, antifibrotic, and antioxidant functions. Here, using genomics analysis, we investigated whether FXR attenuates cisplatin-induced AKI through the regulation of ferroptosis. The increased blood urea nitrogen, serum creatinine and ferroptotic responses in cisplatin-induced AKI mice were attenuated by treatment with FXR agonist, GW4064, while those were exacerbated in FXR knockout mice. Using RNA-sequencing analysis, we found novel target genes for FXR associated with ferroptosis. FXR agonist treatment increases lipid and glutathione metabolic gene expression and decreases cell death genes expression. This study identifies transcriptional regulation of ferroptosis by FXR as a potential therapeutic target for cisplatin-induced AKI.

2022-07-06 | GSE193860 | GEO

Octanedioic-acid supplementation protects from acute kidney injury via stimulation of renal peroxisomal activity over mitochondrial

Project description:Lysine succinylation is a posttranslational modification associated with the control of several diseases, including acute kidney injury (AKI). Hypersuccinylation favors peroxisomal fatty acid oxidation (FAO) instead of mitochondrial. In addition, the medium-chain fatty acids (MCFAs) dodecanedioic acid (DC12) and octanedioic acid (DC8), upon FAO, generate succinyl-CoA, resulting in hypersuccinylation. To test the protective roles of MCFAs during AKI, mice were fed with control, 10% DC12, or 10% DC8 diet, then, subjected to either ischemic-AKI , or cisplatin-AKI models. Supplementation was provided until sacrifice. Biochemical, histologic, genetic, and proteomic analysis were performed, the latter involving a lysine-succinylome-based analysis. Both DC8 and DC12 prevented the rise of AKI markers in mice that underwent renal injury. However, DC8 was even more protective against AKI than DC12. Finally, succinylome analysis evidenced that the kidneys of DC8-fed mice showed an extensive succinylation of peroxisomal activity-related proteins, and a decline in mitochondrial FAO, in comparison to control-fed mice. DC8 supplementation drives renal protein hypersuccinylation, promoting a shift from mitochondrial to peroxisomal FAO, and protecting against AKI. DC8 is convenient, inexpensive, easily administered, and efficient. We believe this study could be translated in the future to clinical settings, which would highly benefit patients at high risk of AKI.

2023-02-06 | MSV000091214 | MassIVE

Small GTP-binding protein GDP dissociation stimulator influences cisplatin-induced acute kidney injury via PERK-dependent ER stress

Project description:Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK in vivo and in vitro. Furthermore, we confirmed that smgGDS deficiency aggravated apoptosis and ER stress in vivo and in vitro. And the ER stress inhibitor 4-Phenylbutyric acid and the inhibition of PERK phosphorylation mitigated smgGDS deficiency-induced ER stress related apoptosis following cisplatin treatment, while the eIF2α phosphorylation inhibitor could not reverse the smgGDS deficiency accelerated cell death. Furthermore, the over-expression of smgGDS could reverse the ER stress and apoptosis caused by CDDP. Overall, smgGDS regulated PERK-dependent ER stress and apoptosis, thereby influencing renal damage. This study identified a target for diagnosing and treating cisplatin-induced acute kidney injury.

2024-09-13 | GSE275317 | GEO

RNAseq of renal CD64+CD11b+F4/80hi from adult mice after cisplatin-induced acute kidney injury

Project description:We use bulk RNA sequencing of sorted cells to characterize the gene expression profiles of renal MHCII+/-D11b+F4/80hi cells 72 hours after cisplatin-induced acute kidney injury (AKI). F4/80hi cells are activated after cisplatin induced AKI and start to downregulate MHCII on transcriptional level. Downregulation of MHCII is probably caused by a downregulation/inhibition of its most important transcriptional activator Ciita

2020-01-31 | GSE135921 | GEO

Transcriptome analysis of kidneys of cisplatin (CP)-induced AKI model

Project description:In the cisplatin (CP)-induced AKI model group, the mice were administered CP and DXZ.

2023-07-30 | GSE200801 | GEO