The counter-regulatory arm of the renin-angiotensin system and COVID-19: insights from Gitelman's and Bartter's syndromes

COVID 19, Paxlovid and the lesson from rare genetic diseases with naturally occurring protection from SARS-CoV-2 infection

“…The coronavirus disease 2019 (COVID-19) pandemic, resulting from infection with SARS-CoV-2 has focused intense scientific interest on Angiotensin Converting Enzyme (ACE)2, as it is expressed in the respiratory epithelium, the heart, the kidney and the vascular wall and is used by the SARS-CoV-2 as an entry point into the cells [ 1 ].…”

“…The SARS-CoV-2 entry and replication-transcription mechanism is based in fact on the binding with glycosylated ACE2, whose glycosylation is dependent on the acidic pH environment of the trans Golgi network/post Golgi pathways in the endosomes, and by several proteases including Cathepsin (Cat)-L, whose activity is also dependent on the acidic endosomal pH [ 1 ].…”

“…These surveys found that none of our 128 patients was hospitalized with COVID-19 and the very few patients who tested positive were either asymptomatic or had very minor symptoms [ 3 , 4 ]. This despite the fact that Gitelman and Bartter syndrome patients have higher ACE2 levels than healthy subjects in addition to renin-angiotensin system activation, yet normo/hypotension and chronic metabolic alkalosis [ 1 , 5 ]. Chronic metabolic alkalosis in Getelman and Bartter patients could be the basis for the possible presence of a specific intracellular environment not favorable to SARS-CoV-2 infection [ 4 , 6 ].…”

Rho kinase inhibition: from hypertension to cardiovascular–renal remodeling and more

“…The upregulation of the NO system upon reduced ROCK activity in GS/BS patients parallels exactly the upregulation of the NO system and the increased eNOS gene expression upon ROCK inhibition shown by Li et al [3] in rats. In addition, ROCK inhibition, increasing the level and activity of ACE2 with production of the vasodilator and antiremodeling Ang 1-7 [6], also increased in GS/BS patients [4,7], activates the counterregulatory arm of the RAS as a mechanism involved in the beneficial effects of ROCK inhibition on blood pressure reduction and protection from cardiovascular remodeling [8,9]. Finally and also relevant for the study of Li et al [3], the treatment of essential hypertensive patients with olmesartan, an Ang II type 1 receptor blocker widely used in the treatment of hypertension, which possesses vasoprotective, anti-inflammatory and antiatherosclerotic effects [10][11][12][13], has been shown to reduce/inhibit the ROCK pathway [14].…”

“…Finally and also relevant for the study of Li et al [3], the treatment of essential hypertensive patients with olmesartan, an Ang II type 1 receptor blocker widely used in the treatment of hypertension, which possesses vasoprotective, anti-inflammatory and antiatherosclerotic effects [10][11][12][13], has been shown to reduce/inhibit the ROCK pathway [14]. This joined to the reduced ROCK pathway in GS/BS patients with their lack of hypertension and cardiovascular remodeling and activation of the counterregulatory arm of RAS [4,9], strongly support with data in hypertensive patients and in a human model characterized by activation of antihypertensive, antiatherosclerotic and antiremodeling defenses, the evidence and conclusions of Li et al [3] on the role of ROCK activation in an animal model of apatimibinduced hypertension and vascular remodeling and of antihypertensive and antiremodeling effects of ROCK inhibition with its potential therapeutic value.…”