RT Journal Article
SR Electronic
T1 Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting
JF Pharmacological Reviews
JO Pharmacol Rev
FD American Society for Pharmacology and Experimental Therapeutics
SP 462
OP 505
DO 10.1124/pharmrev.120.000236
VO 74
IS 3
A1 Lin, Hui
A1 Geurts, Frank
A1 Hassler, Luise
A1 Batlle, Daniel
A1 Mirabito Colafella, Katrina M.
A1 Denton, Kate M.
A1 Zhuo, Jia L.
A1 Li, Xiao C.
A1 Ramkumar, Nirupama
A1 Koizumi, Masahiro
A1 Matsusaka, Taiji
A1 Nishiyama, Akira
A1 Hoogduijn, Martin J.
A1 Hoorn, Ewout J.
A1 Danser, A.H. Jan
A2 Touyz, Rhian
YR 2022
UL http://pharmrev.aspetjournals.org/content/74/3/462.abstract
AB 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.