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AKI in Patients With SARS-CoV-2 Is Significantly Associated With Mitochondrial Dysfunction and ER Stress
Journal of the American Society of Nephrology ; 33:72, 2022.
Article in English | EMBASE | ID: covidwho-2125201
ABSTRACT

Background:

AKI is a common complication of COVID-19. The peripheral blood molecular signatures are unknown and could unveil potential therapeutic targets. Method(s) We enrolled a prospective patient cohort of 283 patients with COVID-19 (Mar 24-Aug 26, 2020), with blood samples from Mount Sinai Biobank. We determined AKI severity using KDIGO criteria on admission parameters. 31 patients with severe AKI (AKI 2-3) were defined as cases. We then performed bulk peripheral RNA sequencing and fit a multivariate linear regression model adjusting for key covariates. We also performed cell-type deconvolution following to adjust for neutrophils, and whole blood cells. We considered a significant p-value (0.05) after Bonferroni correction and then used ingenuity pathway analysis (IPA) to analyze differentially expressed genes. Result(s) Patients who developed AKI were significantly older (67 vs. 60 yrs.) and had a greater prevalence of type 2 diabetes (37% vs 20%), and chronic kidney disease (20% vs 4%) vs. controls. Of the 18539 genes in the analysis, 1597 were upregulated and 1267 were downregulated after Bonferroni correction. Top canonical pathways (Fig 1) showed significantly downregulated genes including EIF2, eIF4, and p70S6K via activation of ATF6, a marker of ER stress. Potential mechanisms displayed by our analyses include upregulation of the NF-KB inhibitor and IL6 pathways. Genes involved in oxidative Phosphorylation and mitochondrial dysfunction were heavily downregulated and there was upregulation of markers of kidney cell necrosis. In contrast, upregulated genes CRK and TIMP2 have been previously implicated in kidney injury and progression. Downregulated mTOR pathway is responsible for the activation of the ER stress response via the eIF2/4 complex which is also supported by our finding of upregulated NRF2- transcriptional pathway. Conclusion(s) Transcriptomic analysis of AKI in COVID-19 revealed evidence of mitochondrial dysfunction driven by ER stress and immune-mediated pathways. Addressing these pathways could aide development of targeted therapies. (Figure Presented).
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Collection: Databases of international organizations Database: EMBASE Language: English Journal: Journal of the American Society of Nephrology Year: 2022 Document Type: Article

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Collection: Databases of international organizations Database: EMBASE Language: English Journal: Journal of the American Society of Nephrology Year: 2022 Document Type: Article