Glomerular Filtration Rate - Extrinsic Regulation
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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:
Renin secretion: First, reduced renal blood flow induces the juxtaglomerular cells to secrete renin, which is an enzyme.
Angiotensinogen conversion: Within the blood stream, renin catalyzes the conversion of angiotensinogen to angiotensin I, which is a hormone with only mild vasoconstrictor effects.
Angiotensin I conversion: As angtiotensin I travels through the blood, angiotensin-converting enzyme converts angiotensin I to angiotensin II.
Angiotensin II: Angiotensin II has widespread effects throughout the body that raise blood volume and pressure
GFR regulation: Arteriole vasoconstriction
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.