Repurposing Zafirlukast Confers Renal Protection in Ischemia-Reperfusion Injury via Suppressing Macrophage METosis
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PROVIDER: PRJNA1288531 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Repurposing Zafirlukast Confers Renal Protection in Ischemia-Reperfusion Injury via Suppressing Macrophage METosis [RNA-Seq]
| PRJNA1289122 | ENA
Project description:Tacrolimus is widely used to prevent post-transplant acute kidney injury (AKI) but causes severe toxicities (e.g., nephrotoxicity, hyperglycemia). We repurposed zafirlukast (ZFK), an FDA-approved asthma drug, to address this limitation. In a murine kidney ischemia-reperfusion injury (KIRI) model, ZFK significantly attenuated renal dysfunction, reducing serum creatinine and blood urea nitrogen (BUN) to levels comparable to tacrolimus, without inducing metabolic adverse effects. RNA sequencing revealed that ZFK recapitulated tacrolimus’ anti-inflammatory gene signatures while uniquely suppressing macrophage extracellular trap formation (METosis). Mechanistically, ZFK inhibited METosis by downregulating PAD4 and CitH3 expression, confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomics (Tabula Muris and GEO database) identified macrophages as the primary target via CysLT1R antagonism. This study provides the first evidence that ZFK protects against KIRI by targeting METosis, a key driver of sterile inflammation. Given its established safety profile, ZFK could bypass Phase I trials, accelerating clinical translation as a safer alternative to calcineurin inhibitors. Our findings also highlight the broader potential of ZFK in METosis-related diseases (e.g., sepsis, atherosclerosis) and underscore drug repurposing as a strategic approach for rapid therapeutic development.
2025-07-13 | GSE302105 | GEO
Project description:Tacrolimus is widely used to prevent post-transplant acute kidney injury (AKI) but causes severe toxicities (e.g., nephrotoxicity, hyperglycemia). We repurposed zafirlukast (ZFK), an FDA-approved asthma drug, to address this limitation. In a murine kidney ischemia-reperfusion injury (KIRI) model, ZFK significantly attenuated renal dysfunction, reducing serum creatinine and blood urea nitrogen (BUN) to levels comparable to tacrolimus, without inducing metabolic adverse effects. RNA sequencing revealed that ZFK recapitulated tacrolimus’ anti-inflammatory gene signatures while uniquely suppressing macrophage extracellular trap formation (METosis). Mechanistically, ZFK inhibited METosis by downregulating PAD4 and CitH3 expression, confirmed by immunofluorescence and flow cytometry. Single-cell transcriptomics (Tabula Muris and GEO database) identified macrophages as the primary target via CysLT1R antagonism. This study provides the first evidence that ZFK protects against KIRI by targeting METosis, a key driver of sterile inflammation. Given its established safety profile, ZFK could bypass Phase I trials, accelerating clinical translation as a safer alternative to calcineurin inhibitors. Our findings also highlight the broader potential of ZFK in METosis-related diseases (e.g., sepsis, atherosclerosis) and underscore drug repurposing as a strategic approach for rapid therapeutic development.
2025-07-14 | GSE302163 | GEO
Project description:Ischemic preconditioning is effective in limiting subsequent ischemic acute kidney injury in experimental models. microRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. An evaluation was performed of the time- and dose-dependent effects of ischemic preconditioning in a rat model of functional (bilateral) ischemia-reperfusion injury. A short, repetitive sequence of ischemic preconditioning resulted in optimal protection from subsequent ischemia-reperfusion injury. A detailed characterization of microRNA expression in ischemic preconditioning/ischemia-reperfusion injury was performed by small RNA-Seq.
2021-12-31 | E-MTAB-9896 | biostudies-arrayexpress
Project description:Ischemic preconditioning is effective in limiting subsequent ischemic acute kidney injury in experimental models. microRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. An evaluation was performed of the time- and dose-dependent effects of ischemic preconditioning in a rat model of functional (bilateral) ischemia-reperfusion injury. A short, repetitive sequence of ischemic preconditioning resulted in optimal protection from subsequent ischemia-reperfusion injury. A detailed characterization of microRNA expression in ischemic preconditioning/ischemia-reperfusion injury was performed by Exiqon miRCURY microRNA array.
2021-12-31 | E-MTAB-9900 | biostudies-arrayexpress
Project description:Myocardial injury may ultimately lead to adverse ventricular remodeling and development of heart failure (HF), which is a major cause of morbidity and mortality worldwide. Given the slow pace and substantial costs of developing new therapeutics, drug repurposing is an attractive alternative. Studies of many organs, including the heart, highlight the importance of the immune system in modulating injury and repair outcomes. Glatiramer-acetate (GA) is an immunomodulatory drug prescribed for patients with multiple sclerosis. Here we report that short-term GA treatment improves cardiac function and reduces scar area in a mouse model of acute myocardial infarction and a rat model of ischemic HF. We provide mechanistic evidence indicating that in addition to its immunomodulatory functions, GA exerts beneficial pleiotropic effects, including cardiomyocyte protection and enhanced angiogenesis. Overall, these findings highlight the potential repurposing of GA as a future therapy for a myriad of heart diseases.
2024-07-09 | PXD053395 | Pride
Project description:During kidney transplantation, ischemia reperfusion injury (IRI) is inevitable and leads to oxidative stress and inflammation. We investigated the role of macronutrients in the effects of dietary restriction on both a phenotypical and transcriptional level, thereby comparing protective and nonprotective diets in search for pathways and regulators involved in the protection against IRI.
2017-01-20 | GSE65656 | GEO
Project description:Resveratrol improves hepatic ischemia-reperfusion injury (HIRI) through inhibiting neutrophils via suppressing ERK signaling pathway
| PRJNA889405 | ENA
Project description:Ischemia-reperfusion (IR) injury, a ubiquitous consequence of liver transplantation, is a cause of early graft rejection and increased morbidity. At present, there are no effective strategies to reduce hepatic IR injury. Molecular mechanisms that promote cell survival under these circumstances are largely undefined. We examined changes in global gene expression at early reperfusion times to identify potential IR-mediated protective responses. Using a rat model of 30 minutes of 70% warm ischemia followed by reperfusion, RNA for microarray analysis was extracted from the non-ischemic and the ischemic-reperfused lobes at four reperfusion times: 0 (no reperfusion), 0.5, 2, and 6 hours. Differentially expressed genes and pathway analyses were used to identify IR-induced events. The transcriptome of the reperfused lobes was unique and discrete at each reperfusion time, showing no evidence of sustained changes of the gene expression alterations seen at 30 minutes of reperfusion. At all reperfusion times, a significant portion of gene expression changes in the reperfused lobes were present in the non-ischemic lobes. However, the earliest reperfusion time, 30 minutes, showed a marked increase in the expression of a set of immediate-early genes (c-Fos, c-Jun, Atf3, Egr1) that was exclusive to the reperfused lobe. Similarities of gene expression changes in the reperfused and the non-ischemic lobes at each time suggest that hemodynamics and/or circulating factors are potent stimuli in an IR model. However, early reperfusion events appear to reflect a cell-autonomous response that may be protective, thereby representing potential targets to ameliorate IR injury.
2019-12-16 | GSE117915 | GEO
Project description:Time course experiments involving bilateral renal ischemia reperfusion injury (IRI) in C57BL/6J mice (0 hr control, 20 min bilateral ischemia without reperfusion, 4, 16, 24, 36, 48, and 72 hrs post IRI). This dataset also includes IRI at 48 hrs and 72 hrs in Azin1 A-to-I locked and Azin1 A-to-I uneditable mice.
2024-09-30 | GSE267650 | GEO