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Abbreviations
ACE: angiotensin-converting enzyme
ACEI: angiotensin-converting enzyme inhibitor
Ac-SDKP: N-acetyl-seryl-aspartyl-lysyl-proline
ACTH: corticotropin (formerly adrenocorticotropic hormone)
Ang: angiotensin
ARDS: acute respiratory distress syndrome
ARNi: angiotensin receptor–neprilysin inhibitors
ARB: angiotensin receptor blocker
BP: blood pressure
cAMP: cyclic AMP
CoV: coronavirus
COVID-19: coronavirus disease 2019
COX: cyclooxygenase
DRI: direct renin inhibitor
ECM: extracellular matrix
GFR: glomerular filtration rate
GI: gastrointestinal
GPCR: G protein-coupled receptor
GRK: G protein-coupled receptor kinases
HFrEF: heart failure with reduced ejection fraction
IRAP: insulin-regulated aminopeptidase
JG: juxtaglomerular
LDL: low-density lipoprotein
MD: macula densa
MI: myocardial infarction
MRGPRD: Mas-related G protein–coupled receptor D
NE: norepinephrine
NO: nitric oxide
NOS: nitric oxide synthase
NSAID: nonsteroidal anti-inflammatory drug
PAI-1: plasminogen activator inhibitor type 1
PG: prostaglandin
PI3K: phosphoinositide 3-kinase
PL: phospholipase
PRA: plasma renin activity
PRC: plasma renin concentration
(pro)renin: renin and prorenin
PRR: (pro)renin receptor
RAS: renin-angiotensin system
RBF: renal blood flow
ROS: reactive O2 species
SARS: severe acute respiratory syndrome
TGF: transforming growth factor
TPR: total peripheral resistance
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THE RENIN-ANGIOTENSIN SYSTEM
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The renin-angiotensin system (RAS) participates in the pathophysiology of numerous clinical disorders, including diabetic nephropathy, hypertension, congestive heart failure, and myocardial infarction (MI). This role has led to extensive study of the RAS and development of multiple ways to inhibit its actions. This chapter discusses the physiology, biochemistry, and cellular and molecular biology of classical and novel RAS components and pathways. The chapter also discusses the pharmacology and clinical utility of drugs that inhibit the RAS. Therapeutic applications of drugs covered in this chapter are also discussed in Chapters 31, 32, 33. The RAS is sometimes identified as the renin-angiotensin-aldosterone system. Aldosterone, a mineralocorticoid, is discussed in Chapter 50.
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HISTORY
In 1898, Tiegerstedt and Bergman found that saline extracts of the kidney (ren-) contained a pressor substance that they named renin. In 1934, Goldblatt and colleagues found that renal artery constriction produced persistent hypertension in dogs. In 1940, Braun-Menéndez and colleagues in Argentina and Page and Helmer in the U.S. reported that renin was an enzyme that acted on a plasma protein substrate to catalyze the formation of a pressor peptide, which the Argentinian investigators named hypertensin and Page and Helman named angiotonin. This peptide was ultimately renamed angiotensin, and its plasma substrate was called angiotensinogen.
In the 1950s, two forms of angiotensin (Ang) were identified: a decapeptide (AngI) and an octapeptide (AngII) formed by the cleavage of AngI by angiotensin-converting enzyme (ACE), a zinc metalloproteinase discovered by Skeggs in 1956. AngII was the more active form; its synthesis by Schwyzer and Bumpus in 1957 made it available for study. Later research showed that the kidneys are an important site of aldosterone action; angiotensin stimulates its production in humans, and renin secretion increases with depletion of Na+. Thus, the RAS became recognized as a mechanism that stimulates aldosterone synthesis and secretion and an important ...