Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting.

The concept of local formation of angiotensin II in the kidney has changed over the last 10-15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS. SIGNIFICANCE STATEMENT: Angiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.

The Dysregulation of the Renin-Angiotensin System in COVID-19 Studied by Serum Proteomics: Angiotensinogen Increases with Disease Severity.

(1) Background: ACE and CPN serum activity correlated with disease severity in an earlier study of 45 hospitalized COVID-19 patients. The serum protein profile was investigated in the same cohort here to shed more light on the involvement of the renin-angiotensin system (RAS). (2) Methods: High-definition mass spectrometry-based protein expression analysis was performed, followed by multivariate statistical and network analyses. (3) Results: The protein profiles of hospitalized patients (HoP) differed significantly from those of convalescent and healthy probands. Surprisingly, HoP samples separated into six groups according to their protein profiles: group (G) 1 represented the youngest and the least afflicted patients, and G6 the oldest and critically ill patients. At least two major pathophysiological schemes were indicated based on differing involvement of the kallikrein-kinin system (KKS), the RAS and complement activation. The serum angiotensinogen concentration increased with disease severity. (4) Conclusions: The important role of the RAS in the response to COVID-19 infection was substantiated, but other pathways such as the KKS, plasminogen activation and complement activation influence the systemic response to the infection.