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Cisplatin-induced rat model of kidney injury: physiological, functional, histological and gene expression profile evaluations

ABSTRACT: Cisplatin-induced rat model of kidney injury: physiological, functional, histological and gene expression profile evaluations

PROVIDER: PRJNA590234 | ENA |

REPOSITORIES: ENA

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Cisplatin-induced rat model of kidney injury: physiological, functional, histological and gene expression profile evaluations

Project description:Cisplatin is a chemotherapeutic drug used for the treatment of solid tumors and hematological malignancies and it is considered as a gold standard therapy in oncology. Its nephrotoxic effect has been largely investigated in vivo but a comprehensive overview that illustrates the effect of cisplatin not only in kidney but also on the entire organism at the same time is still missing. Here we established a stable model of cisplatin-induced acute renal injury in immune competent Sprague Dawley (SD) rats and described the systemic effects of the aforementioned drug. A broad panel of plasma and urine parameters was checked, the histology of different organs was evaluated and the assessment of renal function was measured by using an innovative transcutaneous device. Additionally gene expression profiling with RNAseq technology was performed. Changes in renal injury markers, such as plasma creatinine and urea and urinary albumin, were detected already 2 days after cisplatin administration. Renal function was seriously compromised and so the cytoarchitecture of the kidney. Inflammation was found in liver, lungs and heart. Gene expression profiling of renal tissue revealed 6333 significant differentially expressed genes, 49 pathways and 14 miRNAs.

2021-02-15 | GSE140601 | GEO

Mouse kidney cisplatin TAILS - The proteome microenvironment determines the protective effect of preconditioning in cisplatin-induced acute kidney injury

Project description:Profiling of proteolytic events mouse kidneys during cisplatin-induced kidney damage. Kidneys from vehicle-treated mice are compared to cisplatin-treated mice and cisplatin treatment in animals preconditioned by hypoxia or calory restriction regimes.

2018-10-29 | PXD007186 | Pride

Transcriptomic dataset after cisplatin induced acute kidney injury

Project description:Cisplatin-induced acute kidney injury (AKI) is one of the most common and severe side effects and can prevent the use of this important agent. Unfortunately, preventive or therapeutic tools to address cisplatin-induced AKI are lacking. Interestingly, in the last decades a row of preconditioning strategies that employ the activation of cellular stress resistance pathways have been shown to be promising approaches to protect from organ injury in rodent models. Here, we characterized both the protective potential and the underlying molecular patterns of two strategies – caloric restriction and hypoxic preconditioning – in mice treated with cisplatin.

2018-11-12 | GSE106993 | GEO

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.

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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.

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Project description:Evaluation and comparison of biological responses of rats and gene expression responses of the kidney in rats exposed to different doses of Cisplatin [CAS:15663-27-1;CHEBI:27899]

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