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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]

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): Homo sapiens

PROVIDER: GSE142134 | 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 [mouse]

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 | GSE142137 | GEO

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

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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

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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.

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

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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

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