Renin-Angiotensin-Aldosterone System: From History to Practice of a Secular Topic

Abstract

Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

Keywords: CKD; ESKD; RAAS; albuminuria; aldosterone.

Figure 1

Figure depicts the steps of the RAAS pathway and shows where RAAS-inhibiting therapies target the pathway. The renin–angiotensinogen–aldosterone pathway starts with renin being released from the juxtraglomerullar cells of the kidney due to decreased renal perfusion or low tubular sodium content. Renin then splits angiotensinogen, which is produced in the liver into angiotensin I. Angiotensin I is further converted into angiotensin II by the angiotensin-converting enzyme (ACE). Angiotensin II is the primary effector of the RAAS by causing (1) systemic arteriolar vasoconstriction, (2) secretion of vasopressin (=ADH) in the posterior lobe of the hypothalamus, (3) aldosterone secretion from the zona glomerulosa of the adrenal gland as well as (4) increased sodium and water reabsorption. These effects are mediated through angiotensin II binding to type 1 and type 2 receptors, which often have opposing responses. Aldosterone goes on to bind the mineralocorticoid receptor (MR), causing epithelial sodium channels (EnaC) to be expressed at the apical membrane of the collecting tubules which induces increased sodium and water reabsorption. Aldosterone can also regulate thirst and salt craving by binding to MR in the brain. In the local brain, RAAS angiotensin II is further converted into angiotensin III by aminopeptidase A (APA). Angiotensin III can increase blood pressure by increasing vasopressin release which inhibits diuresis, stimulating sympathetic tone and vascular resistance as well as stimulating baroreflex function. Endothelin-receptor antagonists block the binding of the vasoconstrictive Endothelin-1 to the Endothelin-receptors A and/or B on smooth muscle cells. ACE = Angiotensin-converting enzyme, ACEi = Angiotensin-converting enzyme inhibitor, ADH = Anti-diuretic hormone, APA = Aminopeptidase A, APAi = Aminopeptidase A inhibitor, ARB = Angiotensin II type 1-receptor-blocker, ARNI = Angiotensin II type 1-receptor-neprilysin-inhibitor, AT1-R = Angiotensin type 1-receptor, AT2-R = Angiotensin type 2-receptor, ERA = Endothelin-receptor antagonist, ET-1 = Endothelin-1, ETA/B = Endothelin-receptor type A or B, MR = Mineralocorticoid receptor, MRA = Mineralocorticoid-receptor antagonist, NEP = neutral peptidase.