Renal Renin Angiotensin System

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Renal Renin Angiotensin System Lisa M.
Harrison-Bernard, Ph.D. LSUHSC, New
Orleans lharris_at_lsuhsc.edu
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Renal Physiology - Lectures

• Physiology of Body Fluids
• Structure Function of the Kidneys
• Renal Clearance Glomerular Filtration
• Regulation of Renal Blood Flow
• Transport of Sodium Chloride
• Transport of Urea, Glucose, Phosphate, Calcium
  Organic Solutes
• Regulation of Potassium Balance
• Regulation of Water Balance
• Transport of Acids Bases
• Integration of Salt Water Balance

Renin-angiotensin system (RAS) discussed in
lecture
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How to Approach Renal Physiology?
Cardiovascular Physiology


Respiratory Physiology
Clinical Medicine


Gross Anatomy
Histology
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Learning Objectives

• Diagram formation of angiotensin II (AngII)
• Identify 3 factors that promote renin release
• Describe influence of AngII on renal blood flow
  (RBF) glomerular filtration rate (GFR)
• Describe effects of AngII on regulation of Na
  reabsorption along nephron
• Explain role of RAS in response to decrease in
  blood volume
• ULTIMATE GOAL TO MAINTAIN EXTRACELLULAR FLUID
  VOLUME (ECFV) BLOOD PRESSURE (BP)

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Renin-Angiotensin System

• RAS Cascade
• Control of Renin Secretion
• Hemodynamic Actions of AngII
• Tubular Actions of AngII
• Role of RAS in ? Effective Circulating Volume

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Renal Failure Patient
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Renin-Angiotensin System

• RAS regulates Na balance, plasma volume
• control of arterial blood pressure
• Renin - rate limiting step AngII formation

Major concern ? ECFV ? BP
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Renin-Angiotensin System
Angiotensinogen (a-2 globulin 453 aa)
Renin Proteolytic Enzyme
Angiotensin I (10 aa)
Angiotensin Converting Enzyme
Angiotensin II (8 aa)
Aldosterone Vasoconstriction ? Sodium reabsorption
Receptor AT1 AT2
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RAS
3
AngII
ACE
2
AngII
4
Aldo
1
RENIN
Rate limiting
? Na H2O Excretion
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Renin-Angiotensin System

• Liver secretes angiotensinogen
• Renin release juxtaglomerular (JG) cells cleaves
  angiotensinogen AngI
• AngI cleaved by ACE AngII (also formed
  kidney)
• AngII - Adrenal gland secretes aldosterone
• NET EFFECT ? Na H2O EXCRETION

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Renin-Angiotensin System

• Renin-Angiotensin System Cascade
• Control of Renin Secretion
• Hemodynamic Actions of AngII
• Tubular Actions of AngII
• Role of RAS in ? Effective Circulating Volume

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Control of Renin Release

• Production of renin rate limiting step AngII
  formation
• importance of regulation
• Perfusion pressure - Intrarenal baroreceptors -
  afferent arterioles - ? BP ? renin
• Sympathetic nerves input to JG cells - ?
  firing ? renin
• Delivery NaCl to macula densa cells - ? NaCl ?
  renin

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Control of Renin Release
1
RENIN

• 1. Renal baroreceptors JG cells afferent
  arteriole
• ? RAP ? stretch
• ? renin release
• ? RAP ? stretch ? Ca2
• ? renin release

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Renal Artery Stenosis

• 1. Renal baroreceptors JG cells afferent
  arteriole detect ? BP
• Constriction aorta above renal arteries
  stenosis or narrowing of renal artery due to
  atherosclerosis
• Stenosis of preglomerular arteries or arterioles
  by fibrosis
• Produces renal hypertension due to ? renin, ?
  AngII
• Treat patient w/ ACE inhibitor or ARB

Renal angiogram
Magnetic resonance angiography
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Control of Renin Release

• 2. Influence of sympathetic nerves on JG cells
• ? activity of nerves
• ? renin secretion
• ? activity of nerves
• ? renin secretion

Fig. 16.5 from Vander, Sherman, and Luciano.
Human Physiology The Mechanisms of Body Function
(8th ed.), 2000.
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Control of Renin Release

• 3. Influence of distal delivery of NaCl
• ? NaCl
• ? renin secretion
• ? NaCl
• renin secretion
• AngII
• BP - maintain tissue perfusion

Macula Densa
Fig. 3B from Park and Harrison-Bernard.
Augmented renal neuronal nitric oxide synthase
and renin protein expression in angiotensin type
1 receptor null mice. J Histochem Cytochem.
56(4)401-414, 2008.
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Feedback from Macula Densa
Fig. 3-8 from Koeppen and Stanton. Renal
Physiology (4th ed.). Mosby Physiology Monograph
Series, 2007.
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Actions of Ang II
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Renin-Angiotensin System (RAS)

• Renin-Angiotensin System Cascade
• Control of Renin Secretion
• Hemodynamic Actions of AngII
• Tubular Actions of AngII
• Role of RAS in ? Effective Circulating Volume

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HEMODYNAMIC Actions of AngII

• vasoconstriction ? TPR ? BP
• constrict afferent efferent arterioles
• ? RBF
• contract mesangial cells - ? Kf ? GFR
• TGF - ? sensitivity
• ? Medullary BF

Reduce RBF GFR
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Mouse In Vitro Blood Perfused Juxtamedullary
Nephron
Efferent Arteriole Response to AngII
20 microns
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Summary Major Renal Hormones
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Renin-Angiotensin System (RAS)

• RAS Cascade
• Control of Renin Secretion
• Hemodynamic Actions of AngII
• Tubular Actions of AngII
• Role of RAS in ? Effective Circulating Volume

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TUBULAR Actions of AngII

• Acts directly tubules
• ? Na reabsorption
• Aldosterone release from adrenal
• ? Na reabsorption

Fig. 33-2 from Boron and Boulpaep. Medical
Physiology (2nd ed.), 2008.
Reduce Salt H2O Excretion
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Tubular Actions of AngII
Tubular Fluid
ISF
Na
Na
1
H

• Enhance Na-H exchanger PT TAL ? Na
  reabsorption

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Tubular Actions of AngII
Tubular Fluid
ISF
Na
2
Na

• Enhance NCC in DT ENaC in CD ? Na
  reabsorption

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Tubular Actions of AngII
Fig. 34-13 from Boron and Boulpaep. Medical
Physiology (2nd ed.), 2008.

• ? TGF Sensitivity
• Net effect ? Na excretion

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Regulation of Na and K Excretion

• ? PK or ? AngII ? Aldosterone
• ? amount of Na/K ATPase basolateral membrane
  distal nephron
• ? activity enzymes Krebs cycle
• ? ATP energy Na-K-ATPase pump

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Regulation of Na and K Excretion

• ? PK or ? AngII ? Aldosterone
• ? expression activation ENaC channels enhances
  Na entry into cell ? lumen negative ?
  K secretion
• ? permeability apical membrane to K by ? K
  channels and ? activation K channels

? Na Reabsorption ? Na Excretion ?
Secretion K ? Excretion K
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Hyperkalemia K Secretion by DT CD

• ? NaK-ATPase activity ? ? Ki ? ?
  electrochemical driving force ? ? K secretion
• ? permeability apical membrane to K
• ? tubular flow ? secreted K flushed downstream
  ? ? K lumen ? ? K secretion

Tubular Fluid
ISF
Na
Na
1
K
3
2
K
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Summary Hormonal Control Na Excretion
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Which patients would benefit from drugs that
block RAS?
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• Patients with
• Hypertension
• Heart failure
• Edema
• Kidney disorders
• Cirrhosis of liver

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Renin-Angiotensin System (RAS)

• Renin-Angiotensin System Cascade
• Control of Renin Secretion
• Hemodynamic Actions of AngII
• Tubular Actions of AngII
• Role of RAS in ? Effective Circulating Volume

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Control Renal Sodium and Water Excretion

• ? Effective circulating volume affects 4
  systems
• RAS
• SNS
• AVP
• ANP

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Volume Expansion - ? Effective Circulating
Volume
Fig. 6-4 from Koeppen and Stanton. Renal
Physiology (4th ed.). Mosby Physiology Monograph
Series, 2007.
? hemodynamics transport ? UNaV ? GFR
X PNa - ? Reabsorption
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Volume Expansion

• ? filtered load Na
• ? PT loop of Henle Na reabsorption
• ? Na delivery to distal nephron
• Net effect
• ? Na H2O excretion

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Volume Contraction - ? Effective Circulating
Volume
Fig. 6-5 from Koeppen and Stanton. Renal
Physiology (4th ed.). Mosby Physiology Monograph
Series, 2007.
? hemodynamics transport ? UNaV ? GFR
X PNa - ? Reabsorption
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Volume Contraction

• ? filtered load Na
• ? PT loop of Henle Na reabsorption
• ? Na delivery to distal nephron
• Net effect
• ? Na H2O excretion

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What Did We Learn Today?

• 3 major mechanisms control renin release JG cells
  (BP, volume, SNS)
• AngII influences salt water excretion by
  kidneys hemodynamic tubular actions
• Reduce urinary salt H2O excretion
• ULTIMATE GOAL TO MAINTAIN ECFV BP