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A novel lncRNA XLOC_032768 rescues cisplatin-induced apoptosis of renal tubular cells and acute kidney injury by repressing TNF-α expression in trans-manner [mouse]

ABSTRACT: The cellular and molecular mechanisms by which cisplatin induces nephrotoxicity have been investigated extensively. However, the role of long non-coding RNAs (lncRNAs) in cisplatin-induced nephrotoxicity has not been received much attention. Here, we explore the functions and underlying mechanisms of a novel lncRNA XLOC_032768 in cisplatin-induced nephrotoxicity. Cisplatin treatment resulted in the apoptosis of renal epithelial cells in a mouse model and human renal proximal tubular epithelial cells (HK-2). By performing differentially expressed genes (DEGs) of the transcriptome data, we found the expression of lncRNA XLOC_032768 was significantly repressed by cisplatin treatment, which was also validated by RT-qPCR experiment of in vivo and in vitro model. Overexpression of lncRNA XLOC_032768 significantly inhibited the cisplatin-induced apoptosis of HK-2 and the expression of biomarkers for cisplatin-induced nephrotoxicity. Results from XLOC_032768 overexpression experiment revealed that XLOC_032768 target the tumor necrosis factor (TNF)-α in trans in HK-2 cells and mouse exposed to cisplatin. The administration of lncRNA XLOC_032768 attenuated renal dysfunction, morphological damage, and renal tubular cell injury, which was accompanied by TNF-α preservation, in a mouse model of cisplatin nephrotoxicity. These data indicate that XLOC_032768 suppressed cisplatin-induced apoptosis of tubular epithelial cells and acute kidney injury via a TNF mechanism. LncRNA XLOC_032768 would be a novel agent to reduce cisplatin-induced nephrotoxicity.

ORGANISM(S): Mus musculus

PROVIDER: GSE142137 | GEO | 2021/07/27

REPOSITORIES: GEO

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A novel lncRNA XLOC_032768 rescues cisplatin-induced apoptosis of renal tubular cells and acute kidney injury by repressing TNF-α expression in trans-manner [human]

Project description:The cellular and molecular mechanisms by which cisplatin induces nephrotoxicity have been investigated extensively. However, the role of long non-coding RNAs (lncRNAs) in cisplatin-induced nephrotoxicity has not been received much attention. Here, we explore the functions and underlying mechanisms of a novel lncRNA XLOC_032768 in cisplatin-induced nephrotoxicity. Cisplatin treatment resulted in the apoptosis of renal epithelial cells in a mouse model and human renal proximal tubular epithelial cells (HK-2). By performing differentially expressed genes (DEGs) of the transcriptome data, we found the expression of lncRNA XLOC_032768 was significantly repressed by cisplatin treatment, which was also validated by RT-qPCR experiment of in vivo and in vitro model. Overexpression of lncRNA XLOC_032768 significantly inhibited the cisplatin-induced apoptosis of HK-2 and the expression of biomarkers for cisplatin-induced nephrotoxicity. Results from XLOC_032768 overexpression experiment revealed that XLOC_032768 target the tumor necrosis factor (TNF)-α in trans in HK-2 cells and mouse exposed to cisplatin. The administration of lncRNA XLOC_032768 attenuated renal dysfunction, morphological damage, and renal tubular cell injury, which was accompanied by TNF-α preservation, in a mouse model of cisplatin nephrotoxicity. These data indicate that XLOC_032768 suppressed cisplatin-induced apoptosis of tubular epithelial cells and acute kidney injury via a TNF mechanism. LncRNA XLOC_032768 would be a novel agent to reduce cisplatin-induced nephrotoxicity.

2021-07-27 | GSE142134 | GEO

CD47 modulates the interaction of γ-catenin with E-cadherin and participates in epithelial–mesenchymal transformation in lipid nephrotoxicity

Project description:Hyperlipidemia, an important risk factor for cardiovascular diseases and end-stage renal disease, often increases renal injury and compromises kidney function. In the present study, the kidney histology analysis in human samples showed that high lipid levels induced renal fibrosis. However, the mechanism of lipid nephrotoxicity remains unknown. We employed mice models of two kinds to further experiments. The kidney histology analysis in mouse showed that high lipid levels induced renal fibrosis that was further confirmed by Western blot and real-time PCR of fibrotic indexes (fibronection, collagenI and α-SMA). In Vitro analysis also supported that OX-LDL significantly induced fibrotic response in HK-2 tubular epithelial cells. To further ascertain the mechanism of high lipid-induced fibrosis, RNA-sequencing (RNA-Seq) was performed. Combined the Gene Ontology (GO) analysis results of differentially expressed mRNAs obtained by RNA-Seq with the results of LC-MS/MS and STRING Functional Association Networks showed that CD47 modulated the interaction of γ-catenin with E-cadherin and participated in epithelial–mesenchymal transformation in lipid nephrotoxicity. The inhibition of CD47 expression by transfected with shRNA plasmid or treated with anti-CD47 antibody in OX-LDL-treated tubular epithelial cells restored the expression of E-cadherin and attenuated renal injury including fibrosis and inflammatory response. These findings indicate that CD47 may be a therapeutic potential target for long-term lipid abuse-induced kidney injury.

2021-03-10 | GSE161737 | GEO

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

Pregnane X Receptor (PXR) protects against cisplatin-induced acute kidney injury

Project description:Background: Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many nonxenobiotic functions including the regulation of cell proliferation, inflammatory response and glucose and lipid metabolism. Methods: In this study, we aimed to investigate the role of PXR in cisplatin-induced nephrotoxicity. CAKI model was performed in wild-type or PXR knockout mice. Pregnenolone 16α-carbonitrile (PCN), a mouse PXR specific agonist, was used for PXR activation. The renal function, biochemical, histopathological and molecular alterations were examined in mouse blood, urine or renal tissues. Whole transcriptome analysis was performed by RNA sequencing. Dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were applied to determine the regulation of PXR on its target genes. Results: We found that PXR activation significantly attenuated CAKI as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative and endoplasmic reticulum stress, and suppressed inflammatory factor expression. RNA sequencing analysis revealed that the renoprotective effect of PXR was associated with multiple crucial signaling pathways. In particular, PXR protected against cisplatin-induced AKI by the activation of PI3K/AKT pathway and the induction of multidrug and toxin extrusion 1 (MATE1), an important transporter mediating cellular excretion of cisplatin, in the kidney. Conclusions: Our results demonstrate that PXR activation can preserve renal function in cisplatin-induced AKI and suggest a possibility of PXR as a novel therapeutic target for cisplatin-induced nephrotoxicity.

2023-03-20 | GSE147256 | GEO

Metabolic characterization of directly reprogrammed renal tubular epithelial cells (iRECs)

Project description:Fibroblasts can be directly reprogrammed to induced renal tubular epithelial cells (iRECs) using four transcription factors. These engineered cells may be used for disease modeling, cell replacement therapy or drug and toxicity testing. Direct reprogramming induces drastic changes in the transcriptional landscape, protein expression, morphological and functional properties of cells. However, how the metabolome is changed by reprogramming and to what degree it resembles the target cell type remains unknown. Using untargeted gas chromatography-mass spectrometry (GC-MS) and targeted liquid chromatography-MS, we characterized the metabolome of mouse embryonic fibroblasts (MEFs), iRECs, mIMCD-3 cells, and whole kidneys. Metabolic fingerprinting can distinguish each cell type reliably, revealing iRECs are most similar to mIMCD-3 cells and clearly separate from MEFs used for reprogramming. Treatment with the cytotoxic drug cisplatin induced typical changes in the metabolic profile of iRECs commonly occurring in acute renal injury. Interestingly, metabolites in the medium of iRECs, but not of mIMCD-3 cells or fibroblast could distinguish treated and non-treated cells by cluster analysis. In conclusion, direct reprogramming of fibroblasts into renal tubular epithelial cells strongly influences the metabolome of engineered cells, suggesting that metabolic profiling may aid in establishing iRECs as in vitro models for nephrotoxicity testing in the future.

2021-08-20 | MTBLS608 | MetaboLights

The circadian clock gene Bmal1 facilitates cisplatin-induced renal injury and hepatization

Project description:Cisplatin is one of the most potent chemotherapy drugs to treat cancers, but its clinical application remains limited due to severe nephrotoxicity. Several approaches have been developed to minimize such side effects, notably including chronotherapy, a well-known strategy based on the circadian clock. However, the component of the circadian clock machinery that particularly responses to the cisplatin stimulation remains unknown, including its functions in cisplatin-induced renal injury. In our present study, we demonstrated that Bmal1, as a key clock gene, was induced by the cisplatin stimulation in the mouse kidney and cultured human HK-2 renal cells. Gain- and loss-of-function studies indicated that Bmal1 facilitated cisplatin-induced renal injury both in vivo and in vitro, by aggravating the cell apoptotic process. More importantly, RNA-seq analysis revealed that Bmal1 triggered the expression of hallmark genes involved in renal hepatization, a critical event accompanied by the injury. At the molecular level, Bmal1 activated the transcription of hepatization-associated genes through direct recruitment to the E-box motifs of their promoters. Our findings suggest that Bmal1, a pivotal mediator induced renal injury in response to cisplatin treatment, and the therapeutic intervention targeting Bmal1 in the kidney may be a promising strategy to minimize the toxic side-effects of cisplatin in its clinical applications.

2020-04-24 | GSE149172 | GEO

Far Infrared Radiation Promotes Renal Proximal Tubule Cell Proliferation Functional Characteristics and Has Protective Effects against Cisplatin Nephrotoxicity

Project description:Far infrared radiation (FIR), a subdivision of the electromagnetic spectrum, has been proved to be beneficial for long-term effects of tissue healing, anti-inflammation, promoting growth, modulating sleep, acceleration of microcirculation, and pain relief. We attempt to study whether FIR would be beneficial for renal proximal tubule cell (RPTC) cultivation and renal tissue engineering. We observed the FIR effects on RPTCs, including cell viability, functional characteristics, immunofluorescence presentations, and subcellular findings. And the FIR protective effects would be further examined with HK-2 cell (Human proximal tubule cell line) against cisplatin, a nephrotoxic agent. Our study showed that daily exposure to FIR for 30 minutes could significantly increase rabbit RPTC viability in vitro assessed by MTT assay. FIR is not only beneficial in RPTC cell viability. RPTCs with FIR exposure presented higher expression of Na-K ATPase and GLUT1 (Glucose Transporter 1). The finding was documented with western blot analysis with statistical significance. With Q-PCR, CDK5R1, GNAS, NPPB, and TEK expressions were significantly enhanced. With HK-2 cell, the proximal tubule cell line, FIR had protective effects against cisplatin nephrotoxicity through reducing apoptosis. FIR is a potential photomodulation therapy to facilitate RPTC cultivation with higher cell viability and better functional chanacteristics and would possibly be applied in further nephrotoxicity protection and other cisplatin-sensitive cell protection.

2017-09-05 | GSE98096 | GEO

Tubular epithelial cells cisplatin and EPC EVs apoptosis

Project description:Renal tubular epithelial cells were treated with cisplatin in presence or absence of EPC-derived EVs

2013-09-30 | E-MEXP-3981 | biostudies-arrayexpress

RNA-seq analysis revealed that chloroquine(CQ) intervenes nephrotoxicity of nilotinib in an autophagy-independent manner

Project description:Nilotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor for the first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia. However, its nephrotoxicity has become prominent with the increase of clinical use, which greatly limits its long-term application. So far, the mechanism of nilotinib’s nephrotoxicity is still unknown leading to a lack of clinical intervention strategies. Here, we found that nilotinib could promote intrinsic apoptosis of both vascular endothelial cells and renal tubular epithelial cells, which was mediated by the excessive ubiquitin-proteasome degradation of anti-apoptotic protein BCL-XL. Moreover, we confirmed that Chloroquine (CQ) could intervene nilotinib-induced apoptosis by reversing the decreased BCL-XL whose mechanism was not relied on autophagy inhibition. Furthermore, RNA-seq analysis was applied to identify the potential target of CQ and the result suggested that CQ could alleviate nilotinib-induced ANKRD1 reduction. Further, we found ANKRD1 abrogated cell apoptosis by preventing ubiquitination of BCL-XL and hence inhibiting BCL-XL degradation. In conclusion, our research reveals the molecular mechanism of nilotinib’s nephrotoxicity, wherein the excessive degradation of BCL-XL via ubiquitin-proteasome pathway promotes kidney cells apoptosis, and provides CQ analogs as the clinical intervention strategy of nilotinib’s nephrotoxicity whose pharmacological effect is dependent on ANKRD1 instead of autophagy inhibition.

2023-09-20 | GSE212122 | GEO

Gene expression profiles in isolated proximal tubules and whole kidneys of rats after cisplatin-administration

Project description:To clarify the effects of cisplatin (cis-diamminedichloroplatinum II, CDDP) on the gene expression profiles in renal proximal tubules, microarray analyses were carried out using total RNA samples isolated from microdissected proximal tubules and whole kidneys. The molecular events underlying acute kidney injury (AKI) in the proximal tubules of rats with cisplatin-induced nephrotoxicity were successfully clarified with 17,000 transcripts. Renal proximal tubules were isolated under microscopy, and transcriptome data were collected with Rat Genome Survey MicroarrayÂ® (Applied Biosystems)

2013-12-24 | E-GEOD-37133 | biostudies-arrayexpress

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