Renin-Angiotensin System Renal Renin Angiotensin System Lisa M. Harrison-Bernard, Ph.D. LSUHSC, New Orleans lharris@lsuhsc.edu Lisa M Harrison-Bernard, PhD

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

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

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)

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

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

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

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

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

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

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

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

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

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

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. 16.5 from Vander, Sherman, and Luciano. Human Physiology: The Mechanisms of Body Function (8th ed.), 2000. Lisa M Harrison-Bernard, PhD

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):401-414, 2008. Lisa M Harrison-Bernard, PhD

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

Actions of Ang II

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

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

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

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

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

Renin-Angiotensin System TUBULAR Actions of AngII Acts directly tubules  Na+ reabsorption Aldosterone release from adrenal Fig. 33-2 from Boron and Boulpaep. Medical Physiology (2nd ed.), 2008. * Reduce Salt & H2O Excretion * Lisa M Harrison-Bernard, PhD

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

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

Tubular Actions of AngII Fig. 34-13 from Boron and Boulpaep. Medical Physiology (2nd ed.), 2008. SNGFR, single nephron GFR  TGF Sensitivity Net effect =  Na+ excretion

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

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

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

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

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

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

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

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

∆ 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

 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

∆ 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

 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

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