SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

Rajasree Menon; Edgar A. Otto; Rachel Sealfon; Viji Nair; Aaron K. Wong; Chandra L. Theesfeld; Xi Chen; Yuan Wang; Avinash S. Boppana; Jinghui Luo; Yingbao Yang; Peter M. Kasson; Jennifer A. Schaub; Celine C. Berthier; Sean Eddy; Chrysta C. Lienczewski; Bradley Godfrey; Susan L. Dagenais; Ryann Sohaney; John Hartman; Damian Fermin; Lalita Subramanian; Helen C. Looker; Jennifer L. Harder; Laura H. Mariani; Jeffrey B. Hodgin; Jonathan Z. Sexton; Christiane E. Wobus; Abhijit S. Naik; Robert G. Nelson; Olga G. Troyanskaya; Matthias Kretzler

doi:10.1016/j.kint.2020.09.015

SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

Rajasree Menon, Edgar A. Otto, Rachel Sealfon, Viji Nair, Aaron K. Wong, Chandra L. Theesfeld, Xi Chen, Yuan Wang, Avinash S. Boppana, Jinghui Luo, Yingbao Yang, Peter M. Kasson, Jennifer A. Schaub, Celine C. Berthier, Sean Eddy, Chrysta C. Lienczewski, Bradley Godfrey, Susan L. Dagenais, Ryann Sohaney, John HartmanDamian Fermin, Lalita Subramanian, Helen C. Looker, Jennifer L. Harder, Laura H. Mariani, Jeffrey B. Hodgin, Jonathan Z. Sexton, Christiane E. Wobus, Abhijit S. Naik, Robert G. Nelson, Olga G. Troyanskaya, Matthias Kretzler

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

COVID-19 morbidity and mortality are increased via unknown mechanisms in patients with diabetes and kidney disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Because ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of kidney biopsies from healthy living donors and patients with diabetic kidney disease revealed ACE2 expression primarily in proximal tubular epithelial cells. This cell-specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin-angiotensin-aldosterone system inhibitors in diabetic kidney disease. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing proximal tubular epithelial cells in diabetic kidney disease (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The diabetic kidney disease ACE2-positive proximal tubular epithelial cell module overlapped with expression patterns seen in SARS-CoV-2–infected cells. Similar cellular programs were seen in ACE2-positive proximal tubular epithelial cells obtained from urine samples of 13 hospitalized patients with COVID-19, suggesting a consistent ACE2-coregulated proximal tubular epithelial cell expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19–related kidney damage.

Original language	English (US)
Pages (from-to)	1502-1518
Number of pages	17
Journal	Kidney International
Volume	98
Issue number	6
DOIs	https://doi.org/10.1016/j.kint.2020.09.015
State	Published - Dec 2020

All Science Journal Classification (ASJC) codes

Nephrology

Keywords

ACE inhibitors
COVID-19
SARS-CoV-2
acute kidney injury
diabetic nephropathy
molecular networks
proximal tubules
scRNAseq

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10.1016/j.kint.2020.09.015

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Menon, R., Otto, E. A., Sealfon, R., Nair, V., Wong, A. K., Theesfeld, C. L., Chen, X., Wang, Y., Boppana, A. S., Luo, J., Yang, Y., Kasson, P. M., Schaub, J. A., Berthier, C. C., Eddy, S., Lienczewski, C. C., Godfrey, B., Dagenais, S. L., Sohaney, R., ... Kretzler, M. (2020). SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease. Kidney International, 98(6), 1502-1518. https://doi.org/10.1016/j.kint.2020.09.015

@article{013e15b8a0f94773b63bab90022acb06,

title = "SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease",

abstract = "COVID-19 morbidity and mortality are increased via unknown mechanisms in patients with diabetes and kidney disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Because ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of kidney biopsies from healthy living donors and patients with diabetic kidney disease revealed ACE2 expression primarily in proximal tubular epithelial cells. This cell-specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin-angiotensin-aldosterone system inhibitors in diabetic kidney disease. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing proximal tubular epithelial cells in diabetic kidney disease (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The diabetic kidney disease ACE2-positive proximal tubular epithelial cell module overlapped with expression patterns seen in SARS-CoV-2–infected cells. Similar cellular programs were seen in ACE2-positive proximal tubular epithelial cells obtained from urine samples of 13 hospitalized patients with COVID-19, suggesting a consistent ACE2-coregulated proximal tubular epithelial cell expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19–related kidney damage.",

keywords = "ACE inhibitors, COVID-19, SARS-CoV-2, acute kidney injury, diabetic nephropathy, molecular networks, proximal tubules, scRNAseq",

author = "Rajasree Menon and Otto, {Edgar A.} and Rachel Sealfon and Viji Nair and Wong, {Aaron K.} and Theesfeld, {Chandra L.} and Xi Chen and Yuan Wang and Boppana, {Avinash S.} and Jinghui Luo and Yingbao Yang and Kasson, {Peter M.} and Schaub, {Jennifer A.} and Berthier, {Celine C.} and Sean Eddy and Lienczewski, {Chrysta C.} and Bradley Godfrey and Dagenais, {Susan L.} and Ryann Sohaney and John Hartman and Damian Fermin and Lalita Subramanian and Looker, {Helen C.} and Harder, {Jennifer L.} and Mariani, {Laura H.} and Hodgin, {Jeffrey B.} and Sexton, {Jonathan Z.} and Wobus, {Christiane E.} and Naik, {Abhijit S.} and Nelson, {Robert G.} and Troyanskaya, {Olga G.} and Matthias Kretzler",

note = "Funding Information: This work was supported in part by the Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases ( DK069062 to HCL and RGN; DK083912 , DK082841 , DK020572 , and DK092926 to RGK), the extramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases R24 DK082841 “ Integrated Systems Biology Approach to Diabetic Microvascular Complications ” and P30 DK081943 “ University of Michigan O'Brien Kidney Translational Core Center ” to MK, via the “Kidney Precision Medicine Project” (KPMP, funded by the following grants from the NIDDK : U2C DK114886 , UH3DK114861 , UH3DK114866 , UH3DK114870 , UH3DK114908 , UH3DK114915 , UH3DK114926 , UH3DK114907 , UH3DK114920 , UH3DK114923 , UH3DK114933 , and UH3DK114937 , with U2C DK114886 and UH3 DK114907 ) to MK and OGT, via the Chan Zuckerberg Initiative “Human Cell Atlas Kidney Seed Network” to MK and OGT, JDRF 5-COE-2019-861-S-B “JDRF and M-Diabetes Center of Excellence at the University of Michigan” to MK, and a COVID grant from amFAR , the Foundation for AIDS Research , to MK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: The authors thank Lois Jones, RN, Enrique Diaz, RN, Bernadine Waseta, and Camille Waseta for performing the studies in the diabetes cohort and the University of Michigan Advanced Genomics Core for providing expert technical assistance with single-cell processing and sequencing. They also thank Dr. Carmen Mirabelli for reviewing this manuscript and providing valuable feedback. This work was supported in part by the Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases (DK069062 to HCL and RGN; DK083912, DK082841, DK020572, and DK092926 to RGK), the extramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases R24 DK082841 ?Integrated Systems Biology Approach to Diabetic Microvascular Complications? and P30 DK081943 ?University of Michigan O'Brien Kidney Translational Core Center? to MK, via the ?Kidney Precision Medicine Project? (KPMP, funded by the following grants from the NIDDK: U2C DK114886, UH3DK114861, UH3DK114866, UH3DK114870, UH3DK114908, UH3DK114915, UH3DK114926, UH3DK114907, UH3DK114920, UH3DK114923, UH3DK114933, and UH3DK114937, with U2C DK114886 and UH3 DK114907) to MK and OGT, via the Chan Zuckerberg Initiative ?Human Cell Atlas Kidney Seed Network? to MK and OGT, JDRF 5-COE-2019-861-S-B ?JDRF and M-Diabetes Center of Excellence at the University of Michigan? to MK, and a COVID grant from amFAR, the Foundation for AIDS Research, to MK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We acknowledge the Kidney Precision Medicine Project represented by the following members: American Association of Kidney Patients, Tampa, FL: Richard Knight; Beth Israel Deaconess, Boston, MA: Stewart Lecker, Isaac Stillman; Boston University, Boston, MA: Sushrut Waikar; Brigham and Women's Hospital, Boston, MA: Gearoid McMahon, Astrid Weins, Samuel Short; Broad Institute, Cambridge, MA: Nir Hacohen, Paul Hoover; Case Western Reserve, Cleveland, OH: Mark Aulisio; Cleveland Clinic, Cleveland, OH: Leslie Cooperman, Leal Herlitz, John O'Toole, Emilio Poggio, John Sedor, Stacey Jolly; Columbia University, New York, NY: Paul Appelbaum, Olivia Balderes, Jonathan Barasch, Andrew Bomback, Pietro A. Canetta, Vivette D. d'Agati, Krzysztof Kiryluk, Satoru Kudose, Karla Mehl, Jai Radhakrishnan, Chenhua Weng; Duke University, Durham, NC: Laura Barisoni; European Molecular Biology Laboratory, Heidelberg, Germany: Theodore Alexandrov; Indiana University, Indianapolis, IN: Tarek Ashkar, Daria Barwinska, Pierre Dagher, Kenneth Dunn, Michael Eadon, Michael Ferkowicz, Katherine Kelly, Timothy Sutton, Seth Winfree; John Hopkins University, Baltimore, MD: Steven Menez, Chirag Parikh, Avi Rosenberg, Pam Villalobos, Rubab Malik, Derek Fine, Mohammed Atta, Jose Manuel Monroy Trujillo; Joslin Diabetes Center, Boston, MA: Alison Slack, Sylvia Rosas, Mark Williams; Mount Sinai, New York, NY: Evren Azeloglu, Cijang (John) He, Ravi Iyengar, Jens Hansen; Ohio State University, Columbus, OH: Samir Parikh, Brad Rovin; Pacific Northwest National Laboratories, Richland, WA: Chris Anderton, Ljiljana Pasa-Tolic, Dusan Velickovic, Jessica Lukowski; Parkland Center for Clinical Innovation, Dallas, TX: George (Holt) Oliver; Patient Partners: Joseph Ardayfio, Jack Bebiak, Keith Brown, Taneisha Campbell, Catherine Campbell, Lynda Hayashi, Nichole Jefferson, Robert Koewler, Glenda Roberts, John Saul, Anna Shpigel, Edith Christine Stutzke, Lorenda Wright, Leslie Miegs, Roy Pinkeney; Princeton University, Princeton, NJ: Rachel Sealfon, Olga Troyanskaya; Providence Medical Research Center, Providence Health Care, Spokane, WA: Katherine Tuttle; Stanford University, Palo Alto, CA: Dejan Dobi, Yury Goltsev; University of California San Diego, La Jolla, CA: Blue Lake, Kun Zhang; University of California San Francisco, San Francisco, CA: Maria Joanes, Zoltan Laszik, Andrew Schroeder, Minnie Sarwal, Tara Sigdel; University of Michigan, Ann Arbor, MI: Ulysses Balis, Victoria Blanc, Oliver He, Jeffrey Hodgin, Matthias Kretzler, Laura Mariani, Rajasree Menon, Edgar Otto, Jennifer Schaub, Becky Steck, Chrysta Lienczewski, Sean Eddy; University of Pittsburgh, Pittsburgh, PA: Michele Elder, Daniel Hall, John Kellum, Mary Kruth, Raghav Murugan, Paul Palevsky, Parmjeet Randhawa, Matthew Rosengart, Sunny Sims-Lucas, Mary Stefanick, Stacy Stull, Mitchell Tublin; University of Washington, Seattle, WA: Charles Alpers, Ian de Boer, Ashveena Dighe, Jonathan Himmelfarb, Robyn Mcclelland, Sean Mooney, Stuart Shankland, Kayleen Williams, Kristina Blank, Jonas Carson, Frederick Dowd, Zach Drager, Christopher Park; UT Health San Antonio, Center for Renal Precision Medicine, San Antonio, TX: Kumar Sharma, Guanshi Zhang, Shweta Bansal, Manjeri Venkatachalam; UT Southwestern Medical Center, Dallas, TX: Asra Kermani, Simon Lee, Christopher Lu, Tyler Miller, Orson Moe, Harold Park, Kamalanathan Sambandam, Francisco Sanchez, Jose Torrealba, Toto Robert, Miguel Vazquez, Nancy Wang; Washington University, St. Louis, MO: Joe Gaut, Sanjay Jain, Anitha Vijayan; and Yale University, New Haven, CT: Randy Luciano, Dennis Moledina, Ugwuowo Ugochukwu, Francis Perry Wilson, Sandy Alfano. Funding Information: MK reports grants from the National Institutes of Health (NIH) and nonfinancial support from the University of Michigan during the conduct of the study as well as grants from JDRF, Astra-Zeneca, NovoNordisk, Eli Lilly, Gilead, Goldfinch Bio, Merck, Chan Zuckerberg Initiative, Janssen, Boehringer-Ingelheim, Moderna, Chinook, amfAR, Angion, RenalytixAI, Retrophin, the European Union Innovative Medicine Initiative, and Certa outside of the submitted work, and has licensed patent PCT/EP2014/073413 “Biomarkers and methods for progression prediction for chronic kidney disease.” OT reports serving on the scientific advisory boards of Caris Life Sciences and GoldFinch Bio, both outside of the submitted work. LHM reports grants from NIH–National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences during the conduct of the study and other research funding from Boehringer Ingelheim, serves on the Reata Pharmaceutical CKD Advisory Board, and has received honoraria for American Society of Nephrology Board Review. SE has served as coinvestigator on grants funded by Gilead Sciences, NovoNordisk, Astra-Zeneca, Jannsen, and Eli Lilly. ASN reports funding from the Michigan Institute of Clinical Health Research, Novartis, and the National Institute of Allergy and Infectious Diseases. Publisher Copyright: {\textcopyright} 2020 International Society of Nephrology",

year = "2020",

month = dec,

doi = "10.1016/j.kint.2020.09.015",

language = "English (US)",

volume = "98",

pages = "1502--1518",

journal = "Kidney International",

issn = "0085-2538",

publisher = "Nature Publishing Group",

number = "6",

}

Menon, R, Otto, EA, Sealfon, R, Nair, V, Wong, AK, Theesfeld, CL, Chen, X, Wang, Y, Boppana, AS, Luo, J, Yang, Y, Kasson, PM, Schaub, JA, Berthier, CC, Eddy, S, Lienczewski, CC, Godfrey, B, Dagenais, SL, Sohaney, R, Hartman, J, Fermin, D, Subramanian, L, Looker, HC, Harder, JL, Mariani, LH, Hodgin, JB, Sexton, JZ, Wobus, CE, Naik, AS, Nelson, RG, Troyanskaya, OG & Kretzler, M 2020, 'SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease', Kidney International, vol. 98, no. 6, pp. 1502-1518. https://doi.org/10.1016/j.kint.2020.09.015

TY - JOUR

T1 - SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

AU - Menon, Rajasree

AU - Otto, Edgar A.

AU - Sealfon, Rachel

AU - Nair, Viji

AU - Wong, Aaron K.

AU - Theesfeld, Chandra L.

AU - Chen, Xi

AU - Wang, Yuan

AU - Boppana, Avinash S.

AU - Luo, Jinghui

AU - Yang, Yingbao

AU - Kasson, Peter M.

AU - Schaub, Jennifer A.

AU - Berthier, Celine C.

AU - Eddy, Sean

AU - Lienczewski, Chrysta C.

AU - Godfrey, Bradley

AU - Dagenais, Susan L.

AU - Sohaney, Ryann

AU - Hartman, John

AU - Fermin, Damian

AU - Subramanian, Lalita

AU - Looker, Helen C.

AU - Harder, Jennifer L.

AU - Mariani, Laura H.

AU - Hodgin, Jeffrey B.

AU - Sexton, Jonathan Z.

AU - Wobus, Christiane E.

AU - Naik, Abhijit S.

AU - Nelson, Robert G.

AU - Troyanskaya, Olga G.

AU - Kretzler, Matthias

N1 - Funding Information: This work was supported in part by the Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases ( DK069062 to HCL and RGN; DK083912 , DK082841 , DK020572 , and DK092926 to RGK), the extramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases R24 DK082841 “ Integrated Systems Biology Approach to Diabetic Microvascular Complications ” and P30 DK081943 “ University of Michigan O'Brien Kidney Translational Core Center ” to MK, via the “Kidney Precision Medicine Project” (KPMP, funded by the following grants from the NIDDK : U2C DK114886 , UH3DK114861 , UH3DK114866 , UH3DK114870 , UH3DK114908 , UH3DK114915 , UH3DK114926 , UH3DK114907 , UH3DK114920 , UH3DK114923 , UH3DK114933 , and UH3DK114937 , with U2C DK114886 and UH3 DK114907 ) to MK and OGT, via the Chan Zuckerberg Initiative “Human Cell Atlas Kidney Seed Network” to MK and OGT, JDRF 5-COE-2019-861-S-B “JDRF and M-Diabetes Center of Excellence at the University of Michigan” to MK, and a COVID grant from amFAR , the Foundation for AIDS Research , to MK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: The authors thank Lois Jones, RN, Enrique Diaz, RN, Bernadine Waseta, and Camille Waseta for performing the studies in the diabetes cohort and the University of Michigan Advanced Genomics Core for providing expert technical assistance with single-cell processing and sequencing. They also thank Dr. Carmen Mirabelli for reviewing this manuscript and providing valuable feedback. This work was supported in part by the Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases (DK069062 to HCL and RGN; DK083912, DK082841, DK020572, and DK092926 to RGK), the extramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases R24 DK082841 ?Integrated Systems Biology Approach to Diabetic Microvascular Complications? and P30 DK081943 ?University of Michigan O'Brien Kidney Translational Core Center? to MK, via the ?Kidney Precision Medicine Project? (KPMP, funded by the following grants from the NIDDK: U2C DK114886, UH3DK114861, UH3DK114866, UH3DK114870, UH3DK114908, UH3DK114915, UH3DK114926, UH3DK114907, UH3DK114920, UH3DK114923, UH3DK114933, and UH3DK114937, with U2C DK114886 and UH3 DK114907) to MK and OGT, via the Chan Zuckerberg Initiative ?Human Cell Atlas Kidney Seed Network? to MK and OGT, JDRF 5-COE-2019-861-S-B ?JDRF and M-Diabetes Center of Excellence at the University of Michigan? to MK, and a COVID grant from amFAR, the Foundation for AIDS Research, to MK. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We acknowledge the Kidney Precision Medicine Project represented by the following members: American Association of Kidney Patients, Tampa, FL: Richard Knight; Beth Israel Deaconess, Boston, MA: Stewart Lecker, Isaac Stillman; Boston University, Boston, MA: Sushrut Waikar; Brigham and Women's Hospital, Boston, MA: Gearoid McMahon, Astrid Weins, Samuel Short; Broad Institute, Cambridge, MA: Nir Hacohen, Paul Hoover; Case Western Reserve, Cleveland, OH: Mark Aulisio; Cleveland Clinic, Cleveland, OH: Leslie Cooperman, Leal Herlitz, John O'Toole, Emilio Poggio, John Sedor, Stacey Jolly; Columbia University, New York, NY: Paul Appelbaum, Olivia Balderes, Jonathan Barasch, Andrew Bomback, Pietro A. Canetta, Vivette D. d'Agati, Krzysztof Kiryluk, Satoru Kudose, Karla Mehl, Jai Radhakrishnan, Chenhua Weng; Duke University, Durham, NC: Laura Barisoni; European Molecular Biology Laboratory, Heidelberg, Germany: Theodore Alexandrov; Indiana University, Indianapolis, IN: Tarek Ashkar, Daria Barwinska, Pierre Dagher, Kenneth Dunn, Michael Eadon, Michael Ferkowicz, Katherine Kelly, Timothy Sutton, Seth Winfree; John Hopkins University, Baltimore, MD: Steven Menez, Chirag Parikh, Avi Rosenberg, Pam Villalobos, Rubab Malik, Derek Fine, Mohammed Atta, Jose Manuel Monroy Trujillo; Joslin Diabetes Center, Boston, MA: Alison Slack, Sylvia Rosas, Mark Williams; Mount Sinai, New York, NY: Evren Azeloglu, Cijang (John) He, Ravi Iyengar, Jens Hansen; Ohio State University, Columbus, OH: Samir Parikh, Brad Rovin; Pacific Northwest National Laboratories, Richland, WA: Chris Anderton, Ljiljana Pasa-Tolic, Dusan Velickovic, Jessica Lukowski; Parkland Center for Clinical Innovation, Dallas, TX: George (Holt) Oliver; Patient Partners: Joseph Ardayfio, Jack Bebiak, Keith Brown, Taneisha Campbell, Catherine Campbell, Lynda Hayashi, Nichole Jefferson, Robert Koewler, Glenda Roberts, John Saul, Anna Shpigel, Edith Christine Stutzke, Lorenda Wright, Leslie Miegs, Roy Pinkeney; Princeton University, Princeton, NJ: Rachel Sealfon, Olga Troyanskaya; Providence Medical Research Center, Providence Health Care, Spokane, WA: Katherine Tuttle; Stanford University, Palo Alto, CA: Dejan Dobi, Yury Goltsev; University of California San Diego, La Jolla, CA: Blue Lake, Kun Zhang; University of California San Francisco, San Francisco, CA: Maria Joanes, Zoltan Laszik, Andrew Schroeder, Minnie Sarwal, Tara Sigdel; University of Michigan, Ann Arbor, MI: Ulysses Balis, Victoria Blanc, Oliver He, Jeffrey Hodgin, Matthias Kretzler, Laura Mariani, Rajasree Menon, Edgar Otto, Jennifer Schaub, Becky Steck, Chrysta Lienczewski, Sean Eddy; University of Pittsburgh, Pittsburgh, PA: Michele Elder, Daniel Hall, John Kellum, Mary Kruth, Raghav Murugan, Paul Palevsky, Parmjeet Randhawa, Matthew Rosengart, Sunny Sims-Lucas, Mary Stefanick, Stacy Stull, Mitchell Tublin; University of Washington, Seattle, WA: Charles Alpers, Ian de Boer, Ashveena Dighe, Jonathan Himmelfarb, Robyn Mcclelland, Sean Mooney, Stuart Shankland, Kayleen Williams, Kristina Blank, Jonas Carson, Frederick Dowd, Zach Drager, Christopher Park; UT Health San Antonio, Center for Renal Precision Medicine, San Antonio, TX: Kumar Sharma, Guanshi Zhang, Shweta Bansal, Manjeri Venkatachalam; UT Southwestern Medical Center, Dallas, TX: Asra Kermani, Simon Lee, Christopher Lu, Tyler Miller, Orson Moe, Harold Park, Kamalanathan Sambandam, Francisco Sanchez, Jose Torrealba, Toto Robert, Miguel Vazquez, Nancy Wang; Washington University, St. Louis, MO: Joe Gaut, Sanjay Jain, Anitha Vijayan; and Yale University, New Haven, CT: Randy Luciano, Dennis Moledina, Ugwuowo Ugochukwu, Francis Perry Wilson, Sandy Alfano. Funding Information: MK reports grants from the National Institutes of Health (NIH) and nonfinancial support from the University of Michigan during the conduct of the study as well as grants from JDRF, Astra-Zeneca, NovoNordisk, Eli Lilly, Gilead, Goldfinch Bio, Merck, Chan Zuckerberg Initiative, Janssen, Boehringer-Ingelheim, Moderna, Chinook, amfAR, Angion, RenalytixAI, Retrophin, the European Union Innovative Medicine Initiative, and Certa outside of the submitted work, and has licensed patent PCT/EP2014/073413 “Biomarkers and methods for progression prediction for chronic kidney disease.” OT reports serving on the scientific advisory boards of Caris Life Sciences and GoldFinch Bio, both outside of the submitted work. LHM reports grants from NIH–National Institute of Diabetes and Digestive and Kidney Diseases and the National Center for Advancing Translational Sciences during the conduct of the study and other research funding from Boehringer Ingelheim, serves on the Reata Pharmaceutical CKD Advisory Board, and has received honoraria for American Society of Nephrology Board Review. SE has served as coinvestigator on grants funded by Gilead Sciences, NovoNordisk, Astra-Zeneca, Jannsen, and Eli Lilly. ASN reports funding from the Michigan Institute of Clinical Health Research, Novartis, and the National Institute of Allergy and Infectious Diseases. Publisher Copyright: © 2020 International Society of Nephrology

PY - 2020/12

Y1 - 2020/12

N2 - COVID-19 morbidity and mortality are increased via unknown mechanisms in patients with diabetes and kidney disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Because ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of kidney biopsies from healthy living donors and patients with diabetic kidney disease revealed ACE2 expression primarily in proximal tubular epithelial cells. This cell-specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin-angiotensin-aldosterone system inhibitors in diabetic kidney disease. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing proximal tubular epithelial cells in diabetic kidney disease (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The diabetic kidney disease ACE2-positive proximal tubular epithelial cell module overlapped with expression patterns seen in SARS-CoV-2–infected cells. Similar cellular programs were seen in ACE2-positive proximal tubular epithelial cells obtained from urine samples of 13 hospitalized patients with COVID-19, suggesting a consistent ACE2-coregulated proximal tubular epithelial cell expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19–related kidney damage.

AB - COVID-19 morbidity and mortality are increased via unknown mechanisms in patients with diabetes and kidney disease. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Because ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of kidney biopsies from healthy living donors and patients with diabetic kidney disease revealed ACE2 expression primarily in proximal tubular epithelial cells. This cell-specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin-angiotensin-aldosterone system inhibitors in diabetic kidney disease. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing proximal tubular epithelial cells in diabetic kidney disease (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The diabetic kidney disease ACE2-positive proximal tubular epithelial cell module overlapped with expression patterns seen in SARS-CoV-2–infected cells. Similar cellular programs were seen in ACE2-positive proximal tubular epithelial cells obtained from urine samples of 13 hospitalized patients with COVID-19, suggesting a consistent ACE2-coregulated proximal tubular epithelial cell expression program that may interact with the SARS-CoV-2 infection processes. Thus SARS-CoV-2 receptor networks can seed further research into risk stratification and therapeutic strategies for COVID-19–related kidney damage.

KW - ACE inhibitors

KW - COVID-19

KW - SARS-CoV-2

KW - acute kidney injury

KW - diabetic nephropathy

KW - molecular networks

KW - proximal tubules

KW - scRNAseq

UR - http://www.scopus.com/inward/record.url?scp=85095824858&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85095824858&partnerID=8YFLogxK

U2 - 10.1016/j.kint.2020.09.015

DO - 10.1016/j.kint.2020.09.015

M3 - Article

C2 - 33038424

AN - SCOPUS:85095824858

VL - 98

SP - 1502

EP - 1518

JO - Kidney International

JF - Kidney International

SN - 0085-2538

IS - 6

ER -

SARS-CoV-2 receptor networks in diabetic and COVID-19–associated kidney disease

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