Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

Lin, Hui; Geurts, Frank; Hassler, Luise; Batlle, Daniel; Colafella, Katrina M Mirabito; Denton, Kate M.; Zhuo, Jia L.; Li, Xiao C.; Ramkumar, Nirupama; Koizumi, Masahiro; Matsusaka, Taiji; Nishiyama, Akira; Hoogduijn, Martin J.; Hoorn, Ewout J.; Danser, A.H. Jan

doi:10.1124/pharmrev.120.000236

Cited by 23 publications

(29 citation statements)

References 476 publications

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“…Evaluation of circulating angiotensins in COVID-19 patients should include the use of extracted plasma to minimize nonspecific or false positives and increase angiotensin concentration, particularly in direct ELISAs with small sample volumes that may fall below the sensitivity of the assay, as well as routinely validate these assays with external peptide standards and chromatographic analysis 16 , 72 Serum for endogenous peptide measurements is not suitable as the lack of peptidase inhibitors and the incubation period required for the clotting of blood may lead to artifactually high levels of Ang II or Ang-(1–7). Moreover, Lin et al 74 note that equilibrium peptide assays in serum only measure soluble components of the RAS ex vivo and may fail to account for processing pathways in vivo that occur within tissues or cells and tissue release of the peptides. Nonspecific assays and inappropriate sample handling applied to the quantification of angiotensins may well contribute to conflicting outcomes regarding the overall status of the RAS in COVID-19 patients, as well as complicate our understanding of the impact of SARS-CoV-2 on the RAS.…”

Section: Caveats To Ras Assessmentmentioning

confidence: 99%

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

Chappell

2023

Circulation Research

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The current epidemic of corona virus disease (COVID-19) has resulted in an immense health burden that became the third leading cause of death and potentially contributed to a decline in life expectancy in the United States. The severe acute respiratory syndrome-related coronavirus-2 binds to the surface-bound peptidase angiotensin-converting enzyme 2 (ACE2, EC 3.4.17.23) leading to tissue infection and viral replication. ACE2 is an important enzymatic component of the renin-angiotensin system (RAS) expressed in the lung and other organs. The peptidase regulates the levels of the peptide hormones Ang II and Ang-(1–7), which have distinct and opposing actions to one another, as well as other cardiovascular peptides. A potential consequence of severe acute respiratory syndrome-related coronavirus-2 infection is reduced ACE2 activity by internalization of the viral-ACE2 complex and subsequent activation of the RAS (higher ratio of Ang II:Ang-[1–7]) that may exacerbate the acute inflammatory events in COVID-19 patients and possibly contribute to the effects of long COVID-19. Moreover, COVID-19 patients present with an array of autoantibodies to various components of the RAS including the peptide Ang II, the enzyme ACE2, and the AT 1 AT 2 and Mas receptors. Greater disease severity is also evident in male COVID-19 patients, which may reflect underlying sex differences in the regulation of the 2 distinct functional arms of the RAS. The current review provides a critical evaluation of the evidence for an activated RAS in COVID-19 subjects and whether this system contributes to the greater severity of severe acute respiratory syndrome-related coronavirus-2 infection in males as compared with females.

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Section: Caveats To Ras Assessmentmentioning

confidence: 99%

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

Chappell

2023

Circulation Research

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“… 46 , 47 It now appears that major determinants of urinary AGT are rather glomerular filtration and megalin-mediated reabsorption, so that particularly under conditions where the glomerular barrier is disturbed, urinary AGT largely represents blood-derived hepatic AGT. 48 Multiple factors determine megalin expression and function, including Ang II and urinary pH. 49 Normally, AGT reabsorption is in the order of 95%, and thus a reduction to 90% or 85% might already double or triple urinary AGT levels.…”

Section: Agt Suppression In Kidney Diseasementioning

confidence: 99%

Angiotensinogen Suppression: A New Tool to Treat Cardiovascular and Renal Disease

Cruz-López

et al. 2022

Hypertension

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Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme, or the angiotensin II receptor. Yet, in particular, for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient noncompliance or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides that inhibit angiotensinogen RNA translation, or small interfering RNA (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, antisense oligonucleotides and small interfering RNA require injections only every few weeks to months, which might reduce noncompliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This review discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.

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“…The physiological function of ACE is achieved mainly through two catalytic domains (ACE-N and ACE-C) ( Lin et al, 2022 ), which do not have identical roles. The ACE C-domain plays a role in converting Ang I to Ang II ( Iwaniak et al, 2014 ).…”

Section: Domain Structures and Biological Functions Of Ace And Ace In...mentioning

confidence: 99%

Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective

et al. 2022

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Angiotensin-converting enzyme (ACE), a zinc metalloprotein, is a central component of the renin–angiotensin system (RAS). It degrades bradykinin and other vasoactive peptides. Angiotensin-converting-enzyme inhibitors (ACE inhibitors, ACEIs) decrease the formation of angiotensin II and increase the level of bradykinin, thus relaxing blood vessels as well as reducing blood volume, lowering blood pressure and reducing oxygen consumption by the heart, which can be used to prevent and treat cardiovascular diseases and kidney diseases. Nevertheless, ACEIs are associated with a range of adverse effects such as renal insufficiency, which limits their use. In recent years, researchers have attempted to reduce the adverse effects of ACEIs by improving the selectivity of ACEIs for structural domains based on conformational relationships, and have developed a series of novel ACEIs. In this review, we have summarized the research advances of ACE inhibitors, focusing on the development sources, design strategies and analysis of structure-activity relationships and the biological activities of ACE inhibitors.

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Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

Cited by 23 publications

References 476 publications

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment

Angiotensinogen Suppression: A New Tool to Treat Cardiovascular and Renal Disease

Small molecule angiotensin converting enzyme inhibitors: A medicinal chemistry perspective

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