The Renin-Angiotensin-Aldosterone Axis

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The Renin-Angiotensin-Aldosterone Axis

• An example of physiological signaling

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Essential Background Information

• Extracellular fluid volume tracks total body Na
  content very closely, so Na regulation ECF
  volume regulation
• The kidney is the organ mainly responsible for
  regulating total body Na and ECF volume, which
  adds up to long-term regulation of blood
  pressure.
• Renal performance is regulated by four main
  signal axes, of which we will look at just one as
  our example.

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How the RAA axis responds to a drop in ECF volume

• Specialized receptors in the kidney sense a drop
  in renal blood flow and respond by secreting more
  of a proteolytic enzyme called renin.
• Renin cleaves off part of a circulating plasma
  protein called angiotensinogen, yielding a
  decapeptide called angiotensin I.
• Ang I is converted to Ang II (an octapeptide) by
  angiotensin converting enzyme (ACE) produced in
  the lungs.
• Ang II has three kinds of effects
• Direct one to increase vascular tone
• Increases secretion of aldosterone by the adrenal
  cortex
• Acts on brain to increase thirst and coordinate
  responses of the other 3 regulatory systems

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Immediate effects of angiotensin II are mediated
by G-protein-coupled AT1 receptors

• AT1 couples to Gq and thus activates
  phospholipase C and increases cytosolic Ca
  concentration, leading to smooth muscle
  contraction.

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long-term effects of AT1 are mediated by tyrosine
kinase-coupledpathway

• Ang II is also a growth factor for vascular
  smooth muscle and myocardium it can do this
  because it is also coupled to a second signaling
  pathway with nuclear consequences the JAK-STAT
  pathway
• Thus the AT1 receptor acts both by G-protein
  mechanism and by a receptor tyrosine kinase-like
  mechanism

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Steps in the Jak-Stat pathway

• Receptor activation allows two inactive Jak
  molecules to bind to the receptors cytoplasmic
  domain.
• Jaks are phosphorylated and then phosphorylate
  each other
• Jaks phosphorylate Stat proteins, which then
  dimerize
• Stat dimers migrate into the nucleus and act as
  transcription activators

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Some consequences of too much ang II, as in
high-renin hypertension

• Vascular pathology increased arterial stiffness
• Myocardial hypertrophy

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The RAA pathway can be inhibited to control
hypertension

• ACE inhibitors effective, but side-effects
  include persistent cough
• Ang1 receptor blockers more expensive, but
  apparently they also lower the risk of
  Alzheimers Disease

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Consequences of AT1 receptor antagonists

• Plasma levels of ang II increase by severalfold
  because a negative feedback of ang II on
  angiotensinogen synthesis is mediated by AT1.
• There is an AT2 receptor that is also coupled to
  growth and inflammation responses in smooth
  muscle and heart, so there is the possibility
  that AT1 receptor blockage will lead to some of
  the long-term possibilities that the therapy
  seeks to avoid.

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Aldosterone is the hormone of Na conservation

• Under normal conditions, a large fraction of the
  Na that is initially filtered by the kidney is
  recovered by constitutive processes in the more
  proximal parts of the renal tubules.
• The relatively small fraction that remains is
  addressed by the distal part of the renal tubule,
  where Na reabsorption is under the control of
  aldosterone.
• note that the kidney behaves as if each Na that
  is resorbed must be matched by one of a
  reabsorbed Cl-, a secreted K, or a secreted H.

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The distal tubular principal cells are important
targets of aldosterone
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The next slide shows

• Why too much glucocorticoid could cause
  hypertension, and how this is prevented normally.
• How it is that if you really like liquorice, you
  could become hypertensive, and also hypokalemic
  and alkalotic.

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Steroid receptors are not totally specific!

• As indicated in the previous slide, many steroids
  can bind with two or more types of steroid
  receptors.
• Thus we could characterize any particular steroid
  pharmacologically as having some amount of each
  of androgenic, estrogenic, glucocorticoid and
  mineralocorticoid-like effects.

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Luteal phase bloating

• One good example of how this works out at the
  whole body level occurs in the latter half of the
  human female menstrual cycle (luteal phase), when
  levels of estradiol and progesterone are both
  elevated. Many women experience fluid retention
  during this part of the cycle because the sex
  steroids can also exert some mineralocorticoid-lik
  e effects.