Renin-Angiotensin-Aldosterone System (RAAS)

  • The Renin-Angiotensin-Aldosteorne System (RAAS) is a multi-hormonal system that coordinates a variety of physiological processes for proper regulation of blood volume and pressure.
  • Overview
    • The architecture of the RAAS System is similar to a cascade with each component stimulating the generation of the next component in the pathway. Although synthesis of aldosterone is the final step in the RAAS cascade, the intermediate component Angiotensin II also has potent physiological effects as discussed in the next section.
  • Renin Release
    • Renin is a protein enzyme synthesized and released by juxtaglomerular cells of the juxtaglomerular apparatus, particularly those which surround the renal afferent arteriole. Released renin flows through the kidneys and from there diffuses throughout the circulation.
  • Angiotensin I Generation
    • Angiotensin I is a peptide hormone which is generated by cleavage of the precursor peptide, angiotensinogen that is synthesized continuously by the liver. Cleavage of angiotensinogen to Angiotensin I is performed by renin and occurs throughout the circulation following renal release of renin.
  • Angiotensin II Generation
    • Angiotensin II is a peptide hormone which is generated by further cleavage of Angiotensin I by the enzyme Angiotensin Converting Enzyme (ACE). The highest proportion of ACE activity is observed in the lung, especially in the endothelium of the pulmonary capillaries. ACE-mediated cleavage of Angiotensin I appears to occur constitutively and is not a subject to regulation; however, inhibition of ACE does represent an important locus of pharmacological modulation of the RAAS. It should be pointed out that although circulating levels of Angiotensin II likely result from this ACE-mediated conversion, direct localized secretion of Angiotensin II appears to occur in a variety of anatomical locations, particularly in the kidney. Consequently, direct localized synthesis and secretion of Angiotensin II may represent an alternative pathway for entry into the RAAS.
  • Aldosterone Release
    • Angiotensin II has a variety of important physiological effects as discussed below; however, one such action is the stimulation of aldosterone synthesis and release by the adrenal cortex. The mechanisms of aldosterone synthesis and release are discussed in more detail in Aldosterone Physiology; however, Angiotensin II appears to promote aldosterone synthesis by stimulating production of "Aldosterone Synthase" the rate-limiting enzyme of aldosterone biosynthesis.
  • Overview
    • The main loci of regulation in the RAAS are the release of renin and synthesis of aldosterone. In contrast, conversion of Angiotensin I to Angiotensin II by ACE appears to occur constitutively and is not subject to regulation.
  • Renin Release
    • From a phenomenological perspective, release of renin appears to be inversely correlated with the systemic arterial pressure. Consequently, at high arterial pressures renin release is decreased whereas at low arterial pressures renin release is increased. The mechanisms which connect systemic arterial pressure to renin release appear to be multifactorial and involve several mechanisms. Firstly, decreased perfusion pressure in the renal afferent arterioles appears to directly induce release of renin by the juxtaglomerular cells which are present within the afferent arteriolar wall. Secondly, SNS fibers appear to innervate the juxtaglomerular cells and can stimulate release of renin by these cells via activation membrane beta1 Receptors. Thirdly, as discussed in Tubuloglomerular Feedback, decreased fluid flow through the distal tubule can stimulate the juxtaglomerular cells to release renin.
    • Scenarios of reduced systemic arterial pressure will stimulate all three of the mechanisms described above. Hypotension will be conducted to the renal arterioles, thus reducing their perfusion pressure, and will also activate baroreceptors to stimulate the SNS as discussed in Systemic Arterial Pressure - Short-term Regulation. Finally, reduced renal perfusion pressure will result in a reduced Glomerular Filtration Rate which will yield reduced distal tubular flow thus activating mechanisms of tubuloglomerular feedback.
  • Aldosterone Synthesis
    • As described above, synthesis of aldosterone is stimulated by the RAAS via direct activation of the adrenal cortex by Angiotensin II. It is important to note that other physiological variables can potently impact the aldosterone release by the adrenal cortices, especially the concentration of ECF potassium as described in external potassium balance. Consequently, the rate of adrenocortical synthesis of aldosterone is a balance between the levels of stimulation by Angiotensin II and the ECF potassium concentration. Although this overlap might appear to result in problematic conflicts in physiological regulation of arterial pressure and potassium concentration, features of potassium excretion by the tubules prevent such issues.
Effects Overview
  • Overview
    • The RAAS coordinates multiple physiological processes which together can potently increase the systemic arterial pressure. Consequently, the RAAS can be thought of as a highly effective negative feedback control circuit, which is activated by reduced arterial pressures and brings about higher arterial pressures, thus playing a major role in long-term regulation of arterial pressure. As discussed below, the physiological actions of the RAAS principally center around modulation of the vasculature and renal urinary excretion. As will become clear the RAAS can be thought of as using a two-pronged strategy to enhance the systemic arterial pressure by enhancing the ECF volume through its renal effects and enhancing the systemic vascular resistance through its cardiovascular effects.
  • Renal Effects
    • The renal effects of the RAAS are due to the combined actions of Angiotensin II and aldosterone which coordinate multiple physiological mechanisms to reduce salt and water excretion. Overall, the RAAS serves to significantly sharpen the responsiveness of the pressure natriuresis mechanisms to changes in arterial pressure, and thus allows much better physiological fine-tuning of urinary sodium and water excretion to changes in arterial pressure. Angiotensin II appears to act directly on the proximal tubule to enhance sodium resorption. Because water passively follows resorption of sodium in this segment, the presence of Angiotensin II yields enhanced resorption of both sodium and water in the proximal tubule. Additionally, as discussed in Neuroendocrine Regulation of GFR and RBF, the presence of Angiotensin II results in vasoconstriction principally of the renal efferent arterioles. This effect serves to maintain the glomerular capillary hydrostatic pressure and thus prevent drops in the Glomerular Filtration Rate in contexts of falling arterial pressures.
    • However, the vasoconstriction also increases the filtration fraction in the glomerulus, increasing the oncotic pressure of the blood in the peritubular capillaries and reducing the blood flow through them. Together, these modify peritubular capillary transport in such a way as to enhance peritubular resorption of water and solutes, such as sodium. Finally, Angiotensin II stimulates release of aldosterone] which serves to increase sodium resorption by the late distal tubule and collecting ducts. This action of aldosterone is likely mediated by direct activation of the basolateral NaK ATPase on Principal Cells which consequently enhances luminal secondary active transport of sodium.
    • It should be pointed out that aldosterone also displays important effects on external potassium balance; however, we do not include these in our discussion of the RAAS as the aldosterone secreted in response to changes in potassium is independent of the presence of Angiotensin II. The combined actions of Angiotensin II and aldosterone can potently enhance sodium and water resorption by the tubule and thus prevent losses of ECF volume until further sodium and water can be ingested. Conversely, the absence of Angiotensin II and aldosterone can enhance sodium and water excretion by the kidneys, thus helping eliminate extracellular volume when systemic arterial pressure is elevated.
  • Cardiovascular Effects
    • Systemic levels of Angiotensin II also result in widespread vasoconstriction which can significantly increase the systemic vascular resistance. As discussed in, systemic arterial pressure regulation this increased systemic vascular resistance can serve to increase the systemic arterial pressure.