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 journalArticlepeer-review

4 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 languageEnglish (US)
Pages (from-to)1502-1518
Number of pages17
JournalKidney International
Volume98
Issue number6
DOIs
StatePublished - 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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