Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting

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

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

1 Scopus citations

Abstract

——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 mega-lin-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/nepri-lysin 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.

Original languageEnglish (US)
Pages (from-to)462-505
Number of pages44
JournalPharmacological Reviews
Volume74
Issue number3
DOIs
StatePublished - Jul 1 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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