Modulation of ACE2 in experimental hypertension and in response to treatment with ACE inhibitors and ARBs: potential implications for COVID-19 severity and therapeutic targets

• Grant number: 20/05338-3
• Support Opportunities: Regular Research Grants
• Start date: July 01, 2020
• End date: June 30, 2022
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Adriana Castello Costa Girardi
• Grantee: Adriana Castello Costa Girardi
• Host Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Bruno Caramelli ; Caio de Assis Moura Tavares
• Associated research grant: 16/22140-7 - Molecular bases of renal tubular function and dysfunction, AP.TEM

Abstract

Clinical evidence indicates that hypertensive patients are highly susceptible to infection and the severity of COVID-19, a disease caused by the new SARS coronavirus SARS-Cov-2. The SARS-CoV-2 requires the host protein angiotensin-converting enzyme-2 (ACE2), as a receptor, and the serine protease TMPRSS2, for S protein priming, to gain intracellular entry in the lungs, among other organs in which ACE2 is expressed including heart, kidney, and gut. ACE2, however, is a crucial enzymatic component of the renin-angiotensin system (RAS). ACE2 degrades angiotensin II (Ang II), a peptide with multiple actions that contribute to hypertension development, and generates Ang-(1-7), which antagonizes the effects of Ang II. Moreover, experimental and clinical evidence suggests that RAS blockade by ACE inhibitors (ACEi) and AT1 receptor antagonists (ARBs) may enhance ACE2. In lieu of the fact that many patients with hypertension or other cardiovascular diseases are routinely treated with RAS blockers, new clinical concerns have developed regarding whether these patients are at higher risk for SARS-CoV-2 infection. Notably, there are no studies in animals or humans that have examined the effects of ACEi or BRA on pulmonary ACE2, a possibly route of infection. Additionally, the effects of ARBs and ACEi on ACE2 and TMPRSS2 modulation in hypertensive models is entirely unknown. Moreover, no information is available regarding whether hypertensionand gender, riskfactors that contribute to poor prognosis of patients with COVID-19, modulate ACE2 and/or TMPRSS2. The current study was designed to provide scientific evidence on how tissue and circulating ACE2 is regulated in hypertension and in response to ACEi and ARBs, as well as examine whether gender differences may be involved. The influence of RAS blockade, hypertension, and gender on the modulation of TMPRSS2 will also be elucidated. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TAVARES, CAIO A. M.; BAILEY, MATTHEW A.; GIRARDI, ADRIANA C. C.. Biological Context Linking Hypertension and Higher Risk for COVID-19 Severity. FRONTIERS IN PHYSIOLOGY, v. 11, NOV 19 2020. (20/05338-3, 16/22140-7)

MARTINS, FLAVIA L.; TAVARES, CAIO A. M.; MALAGRINO, PAMELLA A.; RENTZ, THIAGO; BENETTI, ACARIS; RIOS, THIAGO M. S.; PEREIRA, GABRIEL M. D.; CARAMELLI, BRUNO; TEIXEIRA, SAMANTHA K.; KRIEGER, JOSE E.; et al. Sex differences in the lung ACE/ACE2 balance in hypertensive rats. BIOSCIENCE REPORTS, v. 41, n. 12, DEC 2021. (20/05338-3, 16/22140-7)

POLIDORO, JULIANO Z.; LUCHI, WEVERTON M.; SEGURO, ANTONIO CARLOS; MALNIC, GERHARD; GIRARDI, ADRIANA C. C.. Paracrine and endocrine regulation of renal K+ secretion. AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY, v. 322, n. 3, p. 18-pg., 2022-03-01. (20/05338-3, 16/22140-7)