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.