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Multi-omic Characterization of Human Tubular Epithelial Cell Response to Serum

Kevin A. Lidberg, Selvaraj Muthusamy, Mohamed Adil, Ranita S. Patel, Lu Wang, Theo K. Bammler, Jonathan Reichel, Catherine K. Yeung, Jonathan Himmelfarb, View ORCID ProfileEdward J. Kelly, View ORCID ProfileShreeram Akilesh
doi: https://doi.org/10.1101/2021.01.29.428186
Kevin A. Lidberg
1Department of Pharmaceutics, University of Washington, Seattle, Washington US
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Selvaraj Muthusamy
2Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington US
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Mohamed Adil
2Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington US
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Ranita S. Patel
3Seattle Children’s Hospital, Seattle, Washington US
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Lu Wang
4Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington US
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Theo K. Bammler
4Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington US
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Jonathan Reichel
2Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington US
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Catherine K. Yeung
5Department of Pharmacy, University of Washington, Seattle, Washington US
6Kidney Research Institute, Seattle, Washington US
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Jonathan Himmelfarb
6Kidney Research Institute, Seattle, Washington US
7Department of Medicine, Nephology Division, University of Washington, Seattle, Washington US
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Edward J. Kelly
1Department of Pharmaceutics, University of Washington, Seattle, Washington US
6Kidney Research Institute, Seattle, Washington US
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  • For correspondence: EdKelly@uw.edu Shreeram@uw.edu
Shreeram Akilesh
2Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington US
6Kidney Research Institute, Seattle, Washington US
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  • ORCID record for Shreeram Akilesh
  • For correspondence: EdKelly@uw.edu Shreeram@uw.edu
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Abstract

Proteinuria, the spillage of serum proteins into the urine, is a feature of glomerulonephritides, podocyte disorders and diabetic nephropathy. However, the response of tubular epithelial cells to serum protein exposure has not been systematically characterized. Using transcriptomic profiling we studied serum-induced changes in primary human tubular epithelial cells cultured in 3D microphysiological devices. Serum proteins induced cellular proliferation, cytokine secretion and activated a coordinated stress response. We orthogonally confirmed our findings by comparing the transcriptomic and epigenomic landscapes of intact human kidney cortex and isolated tubular epithelial cells cultured in fetal bovine serum. Importantly, key transcriptomic programs in response to either type of serum exposure remained consistent, including comparisons to an established mouse model of kidney injury. This serum-induced transcriptional response was dominated by switching off of nuclear receptor-driven programs and activation of AP-1 and NF-κB signatures in the tubular epigenomic landscape. These features of active regulation were seen at canonical kidney injury genes (HAVCR1) and genes associated with COVID-19 (ACE2, IL6). Our data provide a reference map for dissecting the regulatory and transcriptional response of kidney tubular epithelial cells injury induced by serum.

Competing Interest Statement

Edward J. Kelly and Catherine K. Yeung are consultants for Nortis, Inc.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 29, 2021.
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Multi-omic Characterization of Human Tubular Epithelial Cell Response to Serum
Kevin A. Lidberg, Selvaraj Muthusamy, Mohamed Adil, Ranita S. Patel, Lu Wang, Theo K. Bammler, Jonathan Reichel, Catherine K. Yeung, Jonathan Himmelfarb, Edward J. Kelly, Shreeram Akilesh
bioRxiv 2021.01.29.428186; doi: https://doi.org/10.1101/2021.01.29.428186
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Multi-omic Characterization of Human Tubular Epithelial Cell Response to Serum
Kevin A. Lidberg, Selvaraj Muthusamy, Mohamed Adil, Ranita S. Patel, Lu Wang, Theo K. Bammler, Jonathan Reichel, Catherine K. Yeung, Jonathan Himmelfarb, Edward J. Kelly, Shreeram Akilesh
bioRxiv 2021.01.29.428186; doi: https://doi.org/10.1101/2021.01.29.428186

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