RAAS blockade, kidney disease, and expression ofACE2, the entry receptor for SARS-CoV-2, in kidney epithelial and endothelial cells

Abstract

<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>ACE2</jats:italic> 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 <jats:italic>ACE2</jats:italic> with age and sex at baseline. We observed a statistically significant increase in <jats:italic>ACE2</jats:italic> 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. <jats:italic>ACE2</jats:italic> 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 <jats:italic>ACE2</jats:italic> 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 <jats:italic>ACE2</jats:italic> expression in specific kidney cells, with implications for SARS-CoV-2 entry and pathogenicity.</jats:p>

Obesity-instructed TREM2high macrophages identified by comparative analysis of diabetic mouse and human kidney at single cell resolution

“…All five macrophage subsets were present in the 9 human donors (Table S4), and also identified in a recently assembled kidney meta-atlas (Subramanian et al, 2020), Figure 2C-D, Figure S3D). In the context of cell-cell interactions, VEGFC, a putative LYVE1 ligand, was expressed in PECs and connecting tubule cells (CNT) at greater than 5% prevalence in addition to its expected expression in endothelial cells (ECs) (Figure 2E).…”

A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2

“…Kidney, heart and liver were classified using a similar approach after ambient removal and basic quality control as described above. For classifying kidney nuclei, a published meta-atlas 81 was leveraged as a training dataset. For liver and heart, we used publicly available 10x datasets for training ( Supplemental Table 2 ).…”

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

“…In a small cohort of 11 patients with kidney disease, a statistically significant increase in ACE2 expression with use of ACE-Inhs. or ARBs was detected in renal epithelial and endothelial cells, but the underlying diseases confounded the association ( Subramanian et al, 2020 ). In another study, ACE2 expression slightly, but significantly decreased in nasal cilia of patients taking ACE-Inhs.…”