Urinary Angiotensin-Converting Enzyme 2 in Hypertensive Patients May Be Increased by Olmesartan, an Angiotensin II Receptor Blocker

Furuhashi, Masato; Moniwa, Norihito; Mita, Tomohiro; Fuseya, Takahiro; Ishimura, Shutaro; Ohno, Kohei; Shibata, Satoru; Tanaka, Marenao; Watanabe, Yuki; Akasaka, Hiroshi; Ohnishi, Hirofumi; Yoshida, Hiroyuki; Takizawa, Hideki; Saitoh, Shigeyuki; Ura, Nobuyuki; Shimamoto, Kazuaki; Miura, Tetsuji

doi:10.1093/ajh/hpu086

Cited by 248 publications

(239 citation statements)

References 41 publications

Supporting

Mentioning

218

Contrasting

Unclassified

Order By: Relevance

“…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). Taken together, these observations suggest that chronic AT1R blockade results in ACE2 upregulation in both rats and humans.…”

Section: Sars-cov-2supporting

confidence: 71%

Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

Genevieve

2020

Drug Development Research

715

709

View full text Add to dashboard Cite

At the time of writing this commentary (February 2020), the coronavirus COVID-19 epidemic has already resulted in more fatalities compared with the SARS and MERS coronavirus epidemics combined. Therapeutics that may assist to contain its rapid spread and reduce its high mortality rates are urgently needed. Developing vaccines against the SARS-CoV-2 virus may take many months. Moreover, vaccines based on viral-encoded peptides may not be effective against future coronavirus epidemics, as virus mutations could make them futile. Indeed, new Influenza virus strains emerge every year, requiring new immunizations. A tentative suggestion based on existing therapeutics, which would likely be resistant to new coronavirus mutations, is to use available angiotensin receptor 1 (AT1R) blockers, such as losartan, as therapeutics for reducing the aggressiveness and mortality from SARS-CoV-2 virus infections. This idea is based on observations that the angiotensin-converting enzyme 2 (ACE2) very likely serves as the binding site for SARS-CoV-2, the strain implicated in the current COVID-19 epidemic, similarly to strain SARS-CoV implicated in the 2002-2003 SARS epidemic. This commentary elaborates on the idea of considering AT1Rblockers as tentative treatment for SARS-CoV-2 infections, and proposes a research direction based on datamining of clinical patient records for assessing its feasibility.

show abstract

Section: Sars-cov-2supporting

confidence: 71%

Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

Genevieve

2020

Drug Development Research

715

709

View full text Add to dashboard Cite

show abstract

“…eGFR, estimated glomerular filtration rate; HbA1C, glycated hemoglobin; NEP, neprilysin; NEP_p, plasma NEP; NEP_u, urinary NEP. of urinary ACE2 was investigated in hypertensive patients taking the calcium channel blockers amlodipine and longacting nifedipine, the ACE inhibitor enalapril, and the Ang II receptor blockers losartan, candesartan, valsartan, telmisartan, and olmesartan (13). Only olmesartan was found to increase urinary ACE2 concentration, and other antihypertensive drugs have no such effect.…”

Section: Discussionmentioning

confidence: 99%

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Gutta

Grobe

Kumbaji

et al. 2018

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Angiotensin converting enzyme 2 (ACE2) and neprilysin (NEP) are metalloproteases that are highly expressed in the renal proximal tubules. ACE2 and NEP generate renoprotective angiotensin (1-7) from angiotensin II and angiotensin I, respectively, and therefore could have a major role in chronic kidney disease (CKD). Recent data demonstrated increased urinary ACE2 in patients with diabetes with CKD and kidney transplants. We tested the hypothesis that urinary ACE2, NEP, and a disintegrin and metalloproteinase 17 (ADAM17) are increased and could be risk predictors of CKD in patients with diabetes. ACE2, NEP, and ADAM17 were investigated in 20 nondiabetics (ND) and 40 patients with diabetes with normoalbuminuria (Dnormo), microalbuminuria (Dmicro), and macroalbuminuria (Dmacro) using ELISA, Western blot, and fluorogenic and mass spectrometric-based enzyme assays. Logistic regression model was applied to predict the risk prediction. Receiver operating characteristic curves were drawn, and prediction accuracies were calculated to explore the effectiveness of ACE2 and NEP in predicting diabetes and CKD. Results demonstrated that there is no evidence of urinary ACE2 and ADAM17 in ND subjects, but both enzymes were increased in patients with diabetes, including Dnormo. Although there was no detectable plasma ACE2 activity, there was evidence of urinary and plasma NEP in all the subjects, and urinary NEP was significantly increased in Dmicro patients. NEP and ACE2 showed significant correlations with metabolic and renal characteristics. In summary, urinary ACE2, NEP, and ADAM17 are increased in patients with diabetes and could be used as early biomarkers to predict the incidence or progression of CKD at early stages among individuals with type 2 diabetes.

show abstract

“…The anxiogenic effects of Ang-II induced activation of AT 1a Rs have led several groups to propose the use of angiotensin receptor blockers as therapeutics for anxiety disorders (Khoury et al, 2012; Morrison and Ressler, 2014; Saavedra et al, 2005; Saavedra et al, 2011). Interestingly, patients taking angiotensin receptor blockers had increased ACE2 level (Furuhashi et al, 2015) and activation of ACE2/Ang-(1-7)/MasR axis contributed to the therapeutic effect of ACE inhibition (Luque et al, 1996). These studies, in conjunction with our results, suggest that central augmentation of the ACE2/Ang-(1-7)/MasR axis may complement therapuetic strategies that limit Ang-II induced activation of AT1aR to alleviate stress-related diseases, like anxiety disorders.…”

Section: Discussionmentioning

confidence: 99%

Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors

et al. 2016

View full text Add to dashboard Cite

Over-activation of brain renin-angiotensin system (RAS) has been implicated in the etiology of anxiety disorders. Angiotensin converting enzyme (ACE2) inhibits RAS activity by converting angiotensin II, the effector peptide of RAS, to angiotensin-(1-7), which activates Mas receptors (MasR). Whether increasing brain ACE2 activity reduces anxiety by stimulating central MasR is unknown. To test the hypothesis that increasing brain ACE2 activity reduces anxiety-like behavior via central MasR stimulation, we generated male mice overexpressing ACE2 (ACE2 KI mice) and wild type littermate controls (WT). ACE2 KI mice explored the open arms of the elevated plus maze (EPM) significantly more than WT, suggesting increasing ACE2 activity is anxiolytic. Central delivery of diminazene aceturate, an ACE2 activator, to C57BL/6 mice also reduced anxiety-like behavior in the EPM, but centrally administering ACE2 KI mice A-779, a MasR antagonist, abolished their anxiolytic phenotype, suggesting that ACE2 reduces anxiety-like behavior by activating central MasR. To identify the brain circuits mediating these effects, we measured Fos, a marker of neuronal activation, subsequent to EPM exposure and found that ACE2 KI mice had decreased Fos in the bed nucleus of stria terminalis but had increased Fos in the basolateral amygdala (BLA). Within the BLA, we determined that ~62% of GABAergic neurons contained MasR mRNA and expression of MasR mRNA was upregulated by ACE2 overexpression, suggesting that ACE2 may influence GABA neurotransmission within the BLA via MasR activation. Indeed, ACE2 overexpression was associated with increased frequency of spontaneous inhibitory postsynaptic currents (indicative of presynaptic release of GABA) onto BLA pyramidal neurons and central infusion of A-779 eliminated this effect. Collectively, these results suggest that ACE2 may reduce anxiety-like behavior by activating central MasR that facilitate GABA release onto pyramidal neurons within the BLA.

show abstract

Urinary Angiotensin-Converting Enzyme 2 in Hypertensive Patients May Be Increased by Olmesartan, an Angiotensin II Receptor Blocker

Abstract: In contrast with other antihypertensive drugs, olmesartan may uniquely increase urinary ACE2 level, which could potentially offer additional renoprotective effects.

Cited by 248 publications

References 41 publications

Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

Angiotensin receptor blockers as tentative SARS‐CoV‐2 therapeutics

Increased urinary angiotensin converting enzyme 2 and neprilysin in patients with type 2 diabetes

Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors

Contact Info

Product

Resources

About