TY - JOUR T1 - RAAS blockade, kidney disease, and expression of <em>ACE2</em>, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells JF - bioRxiv DO - 10.1101/2020.06.23.167098 SP - 2020.06.23.167098 AU - Ayshwarya Subramanian AU - Katherine A Vernon AU - Michal Slyper AU - Julia Waldman AU - Malte D Luecken AU - Kirk Gosik AU - Dan Dubinsky AU - Michael S Cuoco AU - Keith Keller AU - Jason Purnell AU - Lan Nguyen AU - Danielle Dionne AU - Orit Rozenblatt-Rosen AU - Astrid Weins AU - Human Cell Atlas Lung Biological Network AU - Aviv Regev AU - Anna Greka Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/07/01/2020.06.23.167098.abstract N2 - SARS-CoV-2, the coronavirus that causes COVID-19, binds to angiotensin-converting enzyme 2 (ACE2) on human cells. Beyond the lung, COVID-19 impacts diverse tissues including the kidney. ACE2 is a key member of the Renin-Angiotensin-Aldosterone System (RAAS) which regulates blood pressure, largely through its effects on the kidney. RAAS blockers such as ACE inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) are widely used therapies for hypertension, cardiovascular and chronic kidney diseases, and therefore, there is intense interest in their effect on ACE2 expression and its implications for SARS-CoV-2 pathogenicity. Here, we analyzed single-cell and single-nucleus RNA-seq of human kidney to interrogate the association of ACEi/ARB use with ACE2 expression in specific cell types. First, we performed an integrated analysis aggregating 176,421 cells across 49 donors, 8 studies and 8 centers, and adjusting for sex, age, donor and center effects, to assess the relationship of ACE2 with age and sex at baseline. We observed a statistically significant increase in ACE2 expression in tubular epithelial cells of the thin loop of Henle (tLoH) in males relative to females at younger ages, the trend reversing, and losing significance with older ages. ACE2 expression in tLoH increases with age in females, with an opposite, weak effect in males. In an independent cohort, we detected a statistically significant increase in ACE2 expression with ACEi/ARB use in epithelial cells of the proximal tubule and thick ascending limb, and endothelial cells, but the association was confounded in this small cohort by the underlying disease. Our study illuminates the dynamics of ACE2 expression in specific kidney cells, with implications for SARS-CoV-2 entry and pathogenicity.Competing Interest StatementA.R. is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas, and an SAB member of ThermoFisher Scientific, Syros Pharmaceuticals, Asimov, and Neogene Therapeutics. O.R.R., is a co-inventor on patent applications filed by the Broad Institute to inventions relating to single cell genomics applications, such as in PCT/US2018/060860 and US Provisional Application No. 62/745,259. P.R.T. is a consultant for Cellarity Inc. ER -