Kidney-targeted renalase agonist prevents cisplatin-induced chronic kidney disease by inhibiting regulated necrosis and inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA727855 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14459677.fastq.gz | Fastqsanger.gz | |||
| SRR14459678.fastq.gz | Fastqsanger.gz | |||
| SRR14459986.fastq.gz | Fastqsanger.gz | |||
| SRR14459987.fastq.gz | Fastqsanger.gz | |||
| SRR14459988.fastq.gz | Fastqsanger.gz |
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Project description:TLR5 agonist CBLB502 has been reported playing protective effects again IR, Here we find CBLB502 might protect cis-platin induced liver and kidney damages.
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Project description: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.
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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.
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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.
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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:Clinical use of a major cancer chemotherapeutic agent, cisplatin, is restricted to dose-limiting renal toxicity. A transcriptomic approach enabled us to extract putative molecules including Pleckstrin homology-like domain, family A, member-3 (Phlda3) contributing to the renal injury. This study investigated the expression of Phlda3 and its regulatory role in tubular injury induced by cisplatin in vivo and in vitro. Real-time PCR and immunoblot assays confirmed that Phlda3 was highly up-regulated in the kidney of mice after a single dose of cisplatin treatment, which preceded increases in the blood urea nitrogen or serum creatinine levels. Particularly, the level of Phlda3 transcript was substantially increased at an early time than that of kidney injury molecule-1, and remained elevated. The effect of cisplatin or acetaminophen treatment on Phlda3 expression in the liver was minimal. Consistently, treatment of NRK52E, a renal tubular cell line, with cisplatin caused increases in Phlda3 mRNA and protein. Knockdown of Phlda3 reversed the decrease in cell viability by cisplatin, supporting the role of Phlda3 in cell death. Akt phosphorylation initially increased after cisplatin treatment, but decreased thereafter. Cisplatin treatment elicited p53 accumulation via mdm2 repression, inducing its target genes, p21 and cyclin G1. Phlda3 deficiency attenuated a decrease in Akt phosphorylation by cisplatin, and prevented p53 accumulation, supporting the role of Phlda3 for p53-mediated tubular cell death. Other renal toxicants, cyclosporine A and CdCl2, also enhanced Phlda3-dependent cell death. Overall, nephrotoxicants including cisplatin induce Phlda3, which leads to p53-mediated tubular cell death via mdm2 repression caused by Akt inhibition. Since the datasets reported on the effect of cisplatin on the kidney were obtained from animals treated with multiple and relatively high doses of cisplatin, we did our cDNA array analyses day 3 after a single dose of cisplatin administration to mice (i.p., 15 mg/kg) and compared the profiles of kidney microarray data. The transcriptomic approach enabled us to find the putative genes encoding molecules contributing to renal injury. Among those genes represented on the microarray, 33 genes were found to be differentially expressed by cisplatin treatment when a 2-fold change cutoff was used. The regulation of exemplary mRNAs identified in the array analysis was confirmed by qRT-PCR. C57BL/6 mice (9 weeks old) were intraperitoneally injected with a single dose of cisplatin (15 mg/kg body weight) or vehicle (saline). The cDNA microarray experiments were done for the kidney of mice 3 days after treatment. Each group contained 3 males.
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