Sex Diversity in Proximal Tubule and Endothelial Gene Expression in Mice with Ischemic Acute Kidney Injury
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PROVIDER: PRJNA604210 | ENA |
REPOSITORIES: ENA
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Project description:Female sex protects against development of acute kidney injury (AKI). While sex hormones may be involved in protection, the role of differential gene expression is unknown. We conducted gene profiling in male and female mice with or without kidney ischemia-reperfusion injury. Mice underwent bilateral renal pedicle clamping (30 min), and tissues were collected 24 hours after reperfusion. RNA-sequencing was performed on proximal tubules and kidney endothelial cells. Female mice were resistant to ischemic injury compared to males, determined by plasma creatinine, histologic scores, neutrophil infiltration, and extent of apoptosis. Sham mice had sex-specific gene disparities in proximal tubule and endothelium, and male mice showed profound gene dysregulation with ischemia-reperfusion compared to females. After ischemia proximal tubules from females exhibited smaller increases compared to males in injury-associated genes Lcn2, Havcr1, and Krt18, and no upregulation of Sox9 or Krt20. Endothelial upregulation of adhesion molecules and cytokines/chemokines occurred in males, but not females. Upregulated genes in male ischemic proximal tubules were linked to tumor necrosis factor and Toll-like receptor pathways, while female ischemic proximal tubules showed upregulated genes in pathways related to transport. The data suggest that sex-specific gene expression profiles in male and female proximal tubule and endothelium may underlie disparities in susceptibility to AKI.
2020-09-09 | GSE144622 | GEO
Project description:Global gene expression in the primary cultured mouse kidney proximal tubule cells treated either DMSO or 1uM GW4064 (a FXR agonist) was compared. Results provide insight into mechanisms underlying effects of FXR activation on gene expression in mouse kidney proximal tubule cells. Male C57/BJ mice aged 6 weeks were sacrificed under anesthesia and kidney proximal tubule cells were cultured until confluent. Cells were treated with either GW4064 (1uM) or equal amount of DMSO and incubated for 24 hours. 4 total RNA samples per group were analyzed and gene expression was compared between the groups.
2015-06-26 | E-GEOD-70296 | biostudies-arrayexpress
Project description:Acute kidney injury (AKI) is a major health care concern. There are no therapies for the treatment of AKI. The primary site of damage during AKI is the proximal tubule, which are highly metabolically active cells that rely upon fatty acids for energy. Proximal tubules are notably mitochondria- and peroxisomes-rich cell type that mediate fatty acid oxidation (FAO). Sirtuins reverse post-translational lysine acylation and control many biological processes including FAO. Sirtuin1 and sirtuin3 are protective against AKI. However, the role of the mitochondrial Sirtuin5 (Sirt5) during AKI has yet to be determined. We found Sirt5 to be highly expressed in the proximal tubule. At baseline Sirtuin5 knockout (Sirt5-/-) animals had modestly decreased mitochondrial function but significantly increased FAO, which was localized to the peroxisome. While no overt kidney phenotype was observed in SIRT5-/- mice, following ischemia reperfusion injury Sirt5-/- animals had significantly improved kidney function and less tissue damage. This coincided with increased peroxisomal activity in the Sirt5-/- proximal tubules in preference to the mitochondria. Here we have identified a novel mechanism driving protection of kidneys from ischemic injury. If this can be harnessed it may prove to be an effective therapeutic.
2019-02-13 | MSV000083439 | MassIVE
Project description:<p><strong>BACKGROUND:</strong> Ischemia/reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). The current standard of care focuses on supporting kidney function, stating the need for more efficient and targeted therapies to enhance repair. Mesenchymal Stromal Cells (MSCs) and their secretome, either as conditioned medium (CM) or extracellular vesicles (EVs), have emerged as promising options for regenerative therapy, however, their full potential in treating AKI remains unknown.</p><p><strong>METHODS:</strong> In this study, we employed an in vitro model of chemically-induced ischemia using antimycin A combined with 2-deoxy-D-glucose to induce ischemic injury in proximal tubule epithelial cells. Afterwards, we evaluated the effects of MSC secretome, CM or EVs obtained from adipose tissue, bone marrow and umbilical cord, on ameliorating the detrimental effects of ischemia. To assess the damage and treatment outcomes, we analyzed cell morphology, mitochondrial health parameters (mitochondrial activity, ATP production, mass and membrane potential) and overall cell metabolism by metabolomics.</p><p><strong>RESULTS:</strong> Our findings show that ischemic injury caused cytoskeletal changes confirmed by disruption of the F-actin network, energetic imbalance as revealed by a 50% decrease in the oxygen consumption rate, increased oxidative stress, mitochondrial dysfunction and reduced cell metabolism. Upon treatment with MSC secretome, the morphological derangements were partly restored and ATP production increased by 40-50%, with umbilical cord-derived EVs being most effective. Furthermore, MSC treatment led to phenotype restoration as indicated by an increase in cell bioenergetics, including increased levels of glycolysis intermediates, as well as an accumulation of antioxidant metabolites.</p><p><strong>CONCLUSION:</strong> Our in vitro model effectively replicated the in vivo-like morphological and molecular changes observed during ischemic injury. Additionally, treatment with MSC secretome ameliorated proximal tubule damage, highlighting its potential as a viable therapeutic option for targeting AKI.</p>
2023-10-16 | MTBLS6279 | MetaboLights
Project description:Injury to the proximal tubule plays a central role in the initiation and progression of kidney fibrosis, and rates of chronic kidney disease progresses approximately 50% faster in males compared to females. We applied Translating Ribosome Affinity Purification (TRAP) followed by RNA-sequencing to characterize the cell-specific proximal tubule transcriptional landscape during fibrosis in male vs. female mice.
2019-09-21 | GSE125015 | GEO
Project description:Background: Acute kidney injury (AKI) is a common clinical event with high morbidity and mortality. We previously demonstrated that injection of cord blood endothelial colony forming cell (ECFC)-derived exosomes, highly enriched in miRNA(miR)-486-5p, prevented ischemic kidney injury in mice. While preclinical models support involvement of several miRs in AKI, the direct effects of miR-486-5p on injury and the kidney transcriptome are unknown. Objective: We studied effects of miR-486-5p in mice with kidney ischemia-reperfusion (IR) injury, and compared the impact of miR-486-5p and ECFC-derived exosomes on the transcriptome of proximal tubules (PTs) and renal endothelial cells. Methods: Adult male mice were subjected to bilateral kidney ischemia (30 min), and injected via tail vein with or without vehicle, miR-486-5p mimic, ECFC-derived exosomes, or scramble miR at the start of reperfusion. Plasma and tissues were collected 24 hrs after reperfusion, and proximal tubular and endothelial cells were isolated for mRNA analysis by RNA-Seq. Results: In mice with kidney IR, injection of miR-486-5p mimic increased levels of miR-486-5p in proximal tubules and endothelial cells, and significantly improved plasma creatinine, histological injury, neutrophil infiltration, and apoptosis, compared to vehicle treatment. MiR-486-5p inhibited expression of phosphatase and tensin homolog (PTEN), and activated AKT. Similar results were observed with exosomes, but scramble miR had no effect. In proximal tubules, miR-486-5p or exosomes reduced expression of several AKI genes (e.g. Lcn2, Havcr1 and Krt20) and caused alterations in apoptotic genes compared to IR alone. In endothelium, miR-486-5p or exosomes caused milder effect than in PTs but still impacting on expression of injury-related genes. Conclusion: MiR-486-5p protects mice against ischemic kidney injury. Both miR-486-5p and exosomes reduce expression of apoptotic genes in PTs and endothelium. The results suggest that systemic delivery of miR-486-5p has therapeutic potential in ischemic AKI.
2023-10-10 | GSE159701 | GEO
Project description:Global gene expression in primary cultured mouse kidney proximal tubule cells treated with either DMSO or 1uM GW4064 (an FXR agonist) was compared. Results provide insight into mechanisms underlying effects of FXR activation on gene expression in mouse kidney proximal tubule cells.
2015-06-26 | GSE70296 | GEO
Project description:Single-cell transcriptomics revealed that gluconeogenesis is impaired in proximal tubule cells during AKI in mice.
2020-06-02 | GSE151167 | GEO
Project description:Translational profiling of proximal tubule in fibrotic kidney
| PRJNA514912 | ENA
Project description:Freshly isolated rat kidney proximal tubules were subjected for transcript profiling. Three microarray experiments were done to obtain the kidney proxmial tubule transcriptome.
2009-01-26 | E-GEOD-13668 | biostudies-arrayexpress