Perinatally administered losartan augments renal ACE2 expression but not cardiac or renal Mas receptor in spontaneously hypertensive rats

Abstract

Since the identification of the alternative angiotensin converting enzyme (ACE)2/Ang-(1-7)/Mas receptor axis, renin-angiotensin system (RAS) is a new complex target for a pharmacological intervention. We investigated the expression of RAS components in the heart and kidney during the development of hypertension and its perinatal treatment with losartan in young spontaneously hypertensive rats (SHR). Expressions of RAS genes were studied by the RT-PCR in the left ventricle and kidney of rats: normotensive Wistar, untreated SHR, SHR treated with losartan since perinatal period until week 9 of age (20 mg/kg/day) and SHR treated with losartan only until week 4 of age and discontinued until week 9. In the hypertrophied left ventricle of SHR, cardiac expressions of Ace and Mas were decreased while those of AT1 receptor (Agtr1a) and Ace2 were unchanged. Continuous losartan administration reduced LV weight (0.43 ± 0.02; P < 0.05 versus SHR) but did not influence altered cardiac RAS expression. Increased blood pressure in SHR (149 ± 2 in SHR versus 109 ± 2 mmHg in Wistar; P < 0.05) was associated with a lower renal expressions of renin, Agtr1a and Mas and with an increase in ACE2. Continuous losartan administration lowered blood pressure to control levels (105 ± 3 mmHg; P < 0.05 versus SHR), however, only renal renin and ACE2 were significantly up-regulated (for both P < 0.05 versus SHR). Conclusively, prevention of hypertension and LV hypertrophy development by losartan was unrelated to cardiac or renal expression of Mas. Increased renal Ace2, and its further increase by losartan suggests the influence of locally generated Ang-(1-7) in organ response to the developing hypertension in SHRs.

Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

“…These opposing actions of ACE and ACE2 were recently reviewed by Smyth, Cañadas-Garre, Cappa, Maxwell, & McKnight, 2019. The AT1R antagonists losartan and olmesartan, commonly applied for reducing blood pressure in hypertensive patients, were shown to increase cardiac ACE2 expression about three-fold following chronic treatment (28 days) after myocardial infarction induced by coronary artery ligation of rats (Ishiyama et al, 2004). Losartan was also shown to upregulate renal ACE2 expression in chronically treated rats (Klimas et al, 2015). In agreement with these observations, higher urinary ACE2 levels were observed in hypertensive patients treated with the AT1R antagonist olmesartan (Furuhashi et al, 2015).…”

A Comprehensive Literature Review on the Clinical Presentation, and Management of the Pandemic Coronavirus Disease 2019 (COVID-19)

“…Contrastingly, patients taking ACEi will have low levels of angiotensin II. There is an upregulation of ACE2 receptors in the kidney and heart in response to ACEi or ARB dosing in rats and humans [46][47][48]. There is no data available on its effect in the alveolar tissue.…”

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“…In a different approach, continuous administration of losartan in spontaneously hypertensive rats decreased blood pressure and increased ACE2 expression, suggesting that increased ACE2/Mas activity could be responsible for reductions in blood pressure. Notably, though there was no increase in the renal ACE2 receptor Mas in this study [39]. Adding further uncertainty, another recent study showed that intrarenal alterations of the ACE2/Ang1–7 complex did not significantly modify the course of malignant hypertension in Cyp1a1-Ren-2 transgenic rats, which have abnormally increased activity of the ACE/Ang II/AT1 pathway [40].…”