1. Renin-Angiotensin System
Renal Renin Angiotensin System
Lisa M. Harrison-Bernard, Ph.D.
LSUHSC, New Orleans
Lisa M Harrison-Bernard, PhD

2. Renin-Angiotensin System
Renal Physiology - Lectures
Renin-Angiotensin System
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
Lisa M Harrison-Bernard, PhD

3. How to Approach Renal Physiology?
Renin-Angiotensin System
How to Approach Renal Physiology?
Cardiovascular
Physiology + +
Respiratory
Physiology
Clinical
Medicine + +
Gross
Anatomy
Histology
Lisa M Harrison-Bernard, PhD

4. 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)

5. Renin-Angiotensin System
RAS Cascade
Control of Renin Secretion
Hemodynamic Actions of AngII
Tubular Actions of AngII
Role of RAS in Δ Effective Circulating Volume

6. Renin-Angiotensin System
** Renal Failure Patient **
Patient Data
 Normal
Plasma (P)K+ 
PUrea BP
PPO4-
Hematocrit 
PHCO3-
PpH
PCa2+
P, plasma concentration
Lisa M Harrison-Bernard, PhD

7. Renin-Angiotensin System
RAS regulates Na+ balance, plasma volume
control of arterial blood pressure
Renin - rate limiting step AngII formation
AA, afferent arteriole
* Major concern =  ECFV  BP *
Lisa M Harrison-Bernard, PhD

8. Renin-Angiotensin System
Angiotensinogen (a-2 globulin; 453 aa)
Renin – Proteolytic Enzyme
Angiotensin I (10 aa)
Angiotensin Converting Enzyme
Angiotensin II (8 aa)
Receptor
AT1
AT2
Aldosterone
Vasoconstriction
 Sodium reabsorption
Lisa M Harrison-Bernard, PhD

9. RAS 3 AngII 2 ACE AngII 4 Aldo 1 RENIN  Na+ & H2O Excretion
ACE, angiotensin converting enzyme; ADH, anti-diuretic hormone; Aldo, aldosterone
Aldo 1
RENIN
*Rate limiting *
 Na+ & H2O Excretion

10. 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

11. Renin-Angiotensin System
Renin-Angiotensin System Cascade
Control of Renin Secretion
Hemodynamic Actions of AngII
Tubular Actions of AngII
Role of RAS in Δ Effective Circulating Volume

12. 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
JGA, juxtaglomerular apparatus

13. Control of Renin Release1
1. “Renal” baroreceptors – JG cells afferent arteriole
 RAP  stretch
 renin release
 RAP  stretch  Ca2+
 renin release
RENIN
RAP, renal arterial pressure

14. Renin-Angiotensin System
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
ARB, angiotensin receptor blocker
Magnetic resonance
angiography
Lisa M Harrison-Bernard, PhD

15. Control of Renin Release
Renin-Angiotensin System
Control of Renin Release
2. Influence of sympathetic nerves on JG cells
 activity of nerves
 renin secretion
 activity of nerves
 renin secretion
Fig from Vander, Sherman, and Luciano. Human Physiology: The Mechanisms of Body Function (8th ed.), 2000.
Lisa M Harrison-Bernard, PhD

16. Control of Renin Release
Renin-Angiotensin System
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): , 2008.
Lisa M Harrison-Bernard, PhD

17. Feedback from Macula Densa
Fig. 3-8 from Koeppen and Stanton. Renal Physiology (4th ed.). Mosby Physiology Monograph Series, 2007.

18. Actions of Ang II

19. Renin-Angiotensin System (RAS)
Renin-Angiotensin System Cascade
Control of Renin Secretion
Hemodynamic Actions of AngII
Tubular Actions of AngII
Role of RAS in Δ Effective Circulating Volume

20. Renin-Angiotensin System
HEMODYNAMIC Actions of AngII
vasoconstriction  TPR  BP
constrict afferent & efferent arterioles
 RBF
contract mesangial cells -  Kf  GFR
TGF -  sensitivity
 Medullary BF
BF, blood flow; Kf, ultrafiltration coefficient;TGF, tubuloglomerularfeedback; TPR, total peripheral resistance
* Reduce RBF & GFR *
Lisa M Harrison-Bernard, PhD

21. Mouse In Vitro Blood Perfused Juxtamedullary Nephron
Renin-Angiotensin System
Mouse In Vitro Blood Perfused Juxtamedullary Nephron
Efferent Arteriole Response to AngII
20 microns
Lisa M Harrison-Bernard, PhD

22. Renin-Angiotensin System
Summary Major Renal Hormones
Vasoconstrictors
 RBF  GFR
Sympathetic nerves
Angiotensin II
Endothelin
AVP
Norepinephrine
Vasodilators
 RBF  GFR
Prostaglandins
Nitric Oxide
Bradykinin
ANP
ANP, atrial natriuretic peptide; AVP, arginine vasopressin
Lisa M Harrison-Bernard, PhD

23. Renin-Angiotensin System (RAS)
RAS Cascade
Control of Renin Secretion
Hemodynamic Actions of AngII
Tubular Actions of AngII
Role of RAS in Δ Effective Circulating Volume

24. Renin-Angiotensin System
TUBULAR Actions of AngII
Acts directly tubules
 Na+ reabsorption
Aldosterone release from adrenal
Fig from Boron and Boulpaep. Medical Physiology (2nd ed.), 2008.
* Reduce Salt & H2O Excretion *
Lisa M Harrison-Bernard, PhD

25. Tubular Actions of AngII
Fluid
ISF
Na+
Na+ 1 H+
ISF, interstitial fluid; PT, proximal tubule; TAL, thick ascending limb
Enhance Na+-H+ exchanger PT & TAL =  Na+ reabsorption

26. Tubular Actions of AngII
Fluid
ISF
Na+ 2
Na+
CD, collecting duct; DT, distal tubule; ENaC, epithelial sodium channel; NCC, sodium-chloride cotransporter
Enhance NCC in DT & ENaC in CD =  Na+ reabsorption

27. Tubular Actions of AngII
Fig from Boron and Boulpaep. Medical Physiology (2nd ed.), 2008.
SNGFR, single nephron GFR
 TGF Sensitivity
Net effect =  Na+ excretion

28. Regulation of Na+ and K+ Excretion
Renin-Angiotensin System
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
Lisa M Harrison-Bernard, PhD

29. Regulation of Na+ and K+ Excretion
Renin-Angiotensin System
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+
Lisa M Harrison-Bernard, PhD

30. Hyperkalemia = K+ Secretion by DT & CD
Renin-Angiotensin System
Hyperkalemia = K+ Secretion by DT & CD
 Na+K+-ATPase activity →  [K+]i →  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 3 K+ 2 K+
Lisa M Harrison-Bernard, PhD

31. Renin-Angiotensin System
Summary Hormonal Control Na+ Excretion
Antinatriuretic
 Na+ Reabsorption
 Na+ Excretion
Aldosterone
Angiotensin II
SNS
AVP
Natriuretic
 Na+ Reabsorption
 Na+ Excretion
ANP
Prostaglandins
Bradykinin
Dopamine
SNS, sympathetic nervous system
Lisa M Harrison-Bernard, PhD

32. Renin-Angiotensin System
Which patients would benefit from drugs that block RAS?
Lisa M Harrison-Bernard, PhD

33. Renin-Angiotensin System
Patients with:
Hypertension
Heart failure
Edema
Kidney disorders
Cirrhosis of liver
Lisa M Harrison-Bernard, PhD

34. Renin-Angiotensin System (RAS)
Renin-Angiotensin System Cascade
Control of Renin Secretion
Hemodynamic Actions of AngII
Tubular Actions of AngII
Role of RAS in Δ Effective Circulating Volume

35. Control Renal Sodium and Water Excretion
Δ Effective circulating volume affects 4 systems:
RAS
SNS
AVP
ANP

36. ∆ hemodynamics & transport  UNaV =  GFR X PNa+ -  Reabsorption
Volume Expansion -  Effective Circulating Volume
Fig. 6-4 from Koeppen and Stanton. Renal Physiology (4th ed.). Mosby Physiology Monograph Series, 2007.
UNaV, rate of Na excretion
∆ hemodynamics & transport
 UNaV =  GFR X PNa+ -  Reabsorption

37.  PT & loop of Henle Na+ reabsorption
Volume Expansion
 filtered load Na+
 PT & loop of Henle Na+ reabsorption
 Na+ delivery to distal nephron
Net effect
=  Na+ & H2O excretion

38. ∆ hemodynamics & transport  UNaV =  GFR X PNa+ -  Reabsorption
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

39.  PT & loop of Henle Na+ reabsorption
Volume Contraction
 filtered load Na+
 PT & loop of Henle Na+ reabsorption
 Na+ delivery to distal nephron
Net effect
=  Na+ & H2O excretion

40. 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