Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injury Article Swipe
Nanditha Anandakrishnan
,
Zhengzi Yi
,
Zeguo Sun
,
Ying Liu
,
Jonathan C. Haydak
,
Sean Eddy
,
Pushkala Jayaraman
,
Stefanie DeFronzo
,
Aparna Saha
,
Qian Sun
,
Yang Dai
,
Anthony Mendoza
,
Gohar Mosoyan
,
Huei Hsun Wen
,
Jennifer A. Schaub
,
Jia Fu
,
Thomas Kehrer
,
Rajasree Menon
,
Edgar A. Otto
,
Bradley Godfrey
,
Mayte Suárez‐Fariñas
,
Sean Leffters
,
Akosua Twumasi
,
Kristin Meliambro
,
Alexander W. Charney
,
Adolfo García‐Sastre
,
Kirk N. Campbell
,
G. Luca Gusella
,
John Cijiang He
,
Lisa Miorin
,
Girish N. Nadkarni
,
Juan P. Wisnivesky
,
Hong Li
,
Matthias Kretzler
,
Steven G. Coca
,
Lili Chan
,
Weijia Zhang
,
Evren U. Azeloglu
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1101/2024.03.18.24304401
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1101/2024.03.18.24304401
COVID-19 has been a significant public health concern for the last four years; however, little is known about the mechanisms that lead to severe COVID-associated kidney injury. In this multicenter study, we combined quantitative deep urinary proteomics and machine learning to predict severe acute outcomes in hospitalized COVID-19 patients. Using a 10-fold cross-validated random forest algorithm, we identified a set of urinary proteins that demonstrated predictive power for both discovery and validation set with 87% and 79% accuracy, respectively. These predictive urinary biomarkers were recapitulated in non-COVID acute kidney injury revealing overlapping injury mechanisms. We further combined orthogonal multiomics datasets to understand the mechanisms that drive severe COVID-associated kidney injury. Functional overlap and network analysis of urinary proteomics, plasma proteomics and urine sediment single-cell RNA sequencing showed that extracellular matrix and autophagy-associated pathways were uniquely impacted in severe COVID-19. Differentially abundant proteins associated with these pathways exhibited high expression in cells in the juxtamedullary nephron, endothelial cells, and podocytes, indicating that these kidney cell types could be potential targets. Further, single-cell transcriptomic analysis of kidney organoids infected with SARS-CoV-2 revealed dysregulation of extracellular matrix organization in multiple nephron segments, recapitulating the clinically observed fibrotic response across multiomics datasets. Ligand-receptor interaction analysis of the podocyte and tubule organoid clusters showed significant reduction and loss of interaction between integrins and basement membrane receptors in the infected kidney organoids. Collectively, these data suggest that extracellular matrix degradation and adhesion-associated mechanisms could be a main driver of COVID-associated kidney injury and severe outcomes.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2024.03.18.24304401
- https://www.medrxiv.org/content/medrxiv/early/2024/03/19/2024.03.18.24304401.full.pdf
- OA Status
- green
- References
- 62
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4392939314
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4392939314Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2024.03.18.24304401Digital Object Identifier
- Title
-
Integrated multiomics implicates dysregulation of ECM and cell adhesion pathways as drivers of severe COVID-associated kidney injuryWork title
- Type
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preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-03-19Full publication date if available
- Authors
-
Nanditha Anandakrishnan, Zhengzi Yi, Zeguo Sun, Ying Liu, Jonathan C. Haydak, Sean Eddy, Pushkala Jayaraman, Stefanie DeFronzo, Aparna Saha, Qian Sun, Yang Dai, Anthony Mendoza, Gohar Mosoyan, Huei Hsun Wen, Jennifer A. Schaub, Jia Fu, Thomas Kehrer, Rajasree Menon, Edgar A. Otto, Bradley Godfrey, Mayte Suárez‐Fariñas, Sean Leffters, Akosua Twumasi, Kristin Meliambro, Alexander W. Charney, Adolfo García‐Sastre, Kirk N. Campbell, G. Luca Gusella, John Cijiang He, Lisa Miorin, Girish N. Nadkarni, Juan P. Wisnivesky, Hong Li, Matthias Kretzler, Steven G. Coca, Lili Chan, Weijia Zhang, Evren U. AzelogluList of authors in order
- Landing page
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https://doi.org/10.1101/2024.03.18.24304401Publisher landing page
- PDF URL
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https://www.medrxiv.org/content/medrxiv/early/2024/03/19/2024.03.18.24304401.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
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https://www.medrxiv.org/content/medrxiv/early/2024/03/19/2024.03.18.24304401.full.pdfDirect OA link when available
- Concepts
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Kidney, Podocyte, Acute kidney injury, Nephron, Biology, Extracellular matrix, Cell biology, Proteomics, Medicine, Internal medicine, Endocrinology, Proteinuria, Gene, BiochemistryTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- References (count)
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62Number of works referenced by this work
- Related works (count)
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10Other works algorithmically related by OpenAlex
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| referenced_works | https://openalex.org/W3120750707, https://openalex.org/W3017730472, https://openalex.org/W3024126428, https://openalex.org/W3167590637, https://openalex.org/W4317037190, https://openalex.org/W3049773056, https://openalex.org/W3082170884, https://openalex.org/W3205194111, https://openalex.org/W4321766222, https://openalex.org/W4385420932, https://openalex.org/W3165727990, https://openalex.org/W4200192515, https://openalex.org/W3133560788, https://openalex.org/W4318195472, https://openalex.org/W4289526446, https://openalex.org/W4380364313, https://openalex.org/W3171623624, https://openalex.org/W3181828173, https://openalex.org/W3182801282, https://openalex.org/W3012539504, https://openalex.org/W3212175417, https://openalex.org/W4200524230, https://openalex.org/W4280608961, https://openalex.org/W2146512944, https://openalex.org/W2158217645, https://openalex.org/W2070050178, https://openalex.org/W2345356016, https://openalex.org/W3145969289, https://openalex.org/W2156665896, https://openalex.org/W2552891007, https://openalex.org/W2025043480, https://openalex.org/W2056151358, https://openalex.org/W1993140311, https://openalex.org/W2033577358, https://openalex.org/W2112975677, https://openalex.org/W3167148659, https://openalex.org/W2466126443, https://openalex.org/W4291036706, https://openalex.org/W4307129290, https://openalex.org/W3092813210, https://openalex.org/W3166627797, https://openalex.org/W3196529166, https://openalex.org/W3204707932, https://openalex.org/W3179888898, https://openalex.org/W4387968644, https://openalex.org/W4224864749, https://openalex.org/W4308523102, https://openalex.org/W3213769184, https://openalex.org/W4295135058, https://openalex.org/W4293473097, https://openalex.org/W2078209296, https://openalex.org/W4290013528, https://openalex.org/W3191104078, https://openalex.org/W3040324376, https://openalex.org/W2084489983, https://openalex.org/W3089938205, https://openalex.org/W3184934265, https://openalex.org/W4223998218, https://openalex.org/W3047897956, https://openalex.org/W2012810666, https://openalex.org/W4200559086, https://openalex.org/W4224989704 |
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