Extrinsic GFR Regulation: Renin Angiotensin System

Renin-angiotensin system

(aka, renin-angiotensin-aldosterone system)

  • Extrinsic mechanism of GFR regulation that is activated when mean arterial pressure drops below 80 mmHg; recall that too-low blood pressure can cause tissue necrosis.
  • To raise blood volume and pressure, the renin-angiotensin system produces hormones that act on multiple organs, including the renal arterioles.
  • Because it requires the production, secretion, and transport of hormones throughout the blood circulation, it is a relatively slow mechanism of GFR regulation.
  • One of these hormones, angiotensin II, has dose-dependent effects on GFR:
    – At low levels, angiotensin II reduces renal blood flow but increases GFR.
    – At higher levels, it reduces both renal blood flow and GFR.

Stimuli for Renin Release:

  • Mechanoreceptors within the juxtaglomerular cells respond to reduced stretch of the afferent arteriole.
  • The macula densa of the distal tubule detects decreased salt concentration of the filtrate, and sends signals to the juxtaglomerular cells.
  • Sympathetic stimulation, which is activated by the baroreceptor reflex, activates beta 1 receptors of the juxtaglomerular cells. Notice that this pathway involves both the nervous and endocrine systems.

Steps of RAS:

  • First, reduced renal blood flow induces the juxtaglomerular cells to secrete renin, which is an enzyme.
  • Within the blood stream, renin catalyzes the conversion of angiotensinogen to angiotensin I, which is a hormone with only mild vasoconstrictor effects.
  • However, as it travels through the blood, *angiotensin-converting enzyme8 converts angiotensin I to angiotensin II.
  • Angiotensin II has widespread effects throughout the body that raise blood volume and pressure

GFR regulation:

  • Angiotensin II induces arteriole vasoconstriction, especially of the efferent arteriole, which has more angiotensin-sensitive receptors than the afferent arteriole does.
  • Reduced blood flow through the efferent arteriole raises hydrostatic capillary pressure within the glomerulus, which helps to maintain GFR within the homeostatic range.
  • However, if efferent arteriole blood flow is reduced too much, the oncotic capillary pressures overwhelm the hydrostatic pressures, and GFR is reduced (filtration pressures are discussed in detail, elsewhere).

Clinical Correlations:

  • RAS can be life-saving in the case of systemic hypotension, but consider the clinical consequences of renal artery stenosis, which reduces blood flow through the renal artery.
    – In response, the renin-angiotensin system activates to elevate blood volume and pressure throughout the body, which can cause renovascular hypertension and kidney damage.
  • A pharmacologic correlate, antihypertensive medications were developed to regulate the renin-angiotensin-aldosterone system, which reduce vasoconstriction and lower blood pressure.
    – Angiotensin converting enzyme inhibitors (ACE inhibitors); inhibit ACE.
    Unfortunately, ACE inhibitors can cause an irritating dry cough,
    So angiotensin 2 receptor inhibitors were also developed to block the angiotensin 2, type 1 receptors.

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