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

Abstract

AbstractCOVID-19 morbidity and mortality is increased in patients with diabetes and kidney disease via unknown mechanisms. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) for entry into host cells. Since ACE2 is a susceptibility factor for infection, we investigated how diabetic kidney disease (DKD) and medications alter ACE2 receptor expression in kidneys. Single cell RNA profiling of healthy living donor (LD) and DKD kidney biopsies revealed ACE2 expression primarily in proximal tubular epithelial cells (PTEC). This cell specific localization was confirmed by in situ hybridization. ACE2 expression levels were unaltered by exposures to renin angiotensin aldosterone system inhibitors in DKD. Bayesian integrative analysis of a large compendium of public -omics datasets identified molecular network modules induced in ACE2-expressing PTEC in DKD (searchable at hb.flatironinstitute.org/covid-kidney) that were linked to viral entry, immune activation, endomembrane reorganization, and RNA processing. The DKD ACE2-positive PTEC module overlapped with expression patterns seen in SARS-CoV-2 infected cells. Similar cellular programs were seen in ACE2-positive PTEC obtained from urine samples of 13 COVID-19 patients who were hospitalized, suggesting a consistent ACE2-coregulated PTEC 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.Translational statementTo understand the overwhelming burden of kidney disease in COVID-19, we mapped the expression of the SARS-CoV-2 receptor, ACE2, in healthy kidney, early diabetic (DKD) and COVID-19 associated kidney diseases. Single cell RNA sequencing of 111035 cells identified ACE2 predominantly in proximal tubular epithelial cells. ACE2 upregulation was observed in DKD, but was not associated with RAAS inhibition, arguing against an increased risk of COVID-19 among patients taking RAAS inhibitors. Molecular network analysis linked ACE2 expression to innate immune response and viral entry machinery, thereby revealing potential therapeutic strategies against COVID-19.