MED 204: RAAS, Fluid Balance

Renin – Angiotensin – Aldosterone System (RAAS)

• The RAAS is described
• The course is named "Renal System Module" with code MED 204
• Lectures are given by Dr. Stephen Keely and Dr. Patrick Walsh in February 2025

Learning Objectives

• Factors that influence the distribution of body water
• Normal range of plasma osmolarity
• Role of sodium and water balance
• RAAS and its key functions
• Mechanisms regulating renin and aldosterone release
• Functions of renin and aldosterone are outlined
• Causes and differences between primary and secondary hyperaldosteronism

Water Distribution

• Intracellular Fluid (ICF) and Interstitial Fluid (IF) movement is driven by osmotic pressure
• IF and Plasma movement is driven by hydrostatic pressure
• Total Body Water (TBW) is distributed between ICF and Extracellular Fluid (ECF)

Body Fluid Volumes

• ICF accounts for 2/3 of TBW
• ECF makes up 1/3 of TBW
• For a 70kg individual:
  • TBW is 42L
  • ICF is 28L (65% of TBW)
  • ECF is 14L (35% of TBW) consisting of:
    • 10.5L Interstitial Fluid (IF)
    • 3L Plasma
    • 0.5L Transcellular Fluid
• Daily ingestion and excretion are both 1-2L

Extracellular Fluid (ECF) Osmolarity

• Consistent solute and electrolyte concentration in ECF is vital for cellular function
• Osmolarity calculated as Amount of solute + electrolytes/ Volume of ECF
• Standard ECF osmolarity is about 300 mOsm/L
• Osmolarity can be derived from plasma concentrations: Osmolarity = 2 x [Na+] + 2 x [K+] + [Glucose] + [Urea]

Renin-Angiotensin System Principle

• The primary role of the renin-angiotensin system is blood pressure and fluid volume control
• Low blood pressure reduces oxygen supply
• Low blood pressure causes concentration issues, nausea, dizziness, and fainting
• RAAS addresses low blood pressure in the short and long term

Renin-Angiotensin System Components

• Renin is produced in the kidney
• Angiotensinogen converted to Angiotensin I by Renin (rate limiting step)
• Angiotensin I is converted to Angiotensin II by Angiotensin Converting Enzyme
• Angiotensinogen is generated in the liver
• Angiotensin II acts on Angiotensin II receptors to:
  • Cause tubular reabsorption, aldosterone secretion and vasoconstriction
  • Induce ADH (vasopressin) release
• These responses lead to an increase in blood pressure

Renin Production

• Synthesised in juxtaglomerular cells as:
  • Preprorenin (406 amino acids)
  • Prorenin (383 amino acids)
• The active version of renin is:
  • 340 amino acids long
  • Stored in secretory granules
  • Released when blood pressure decreases
  • Half-life in bloodstream is ~80 minutes
  • Splits angiotensinogen to form angiotensin I
• Activity of renin-angiotensin system can be measured clinically as plasma renin activity (PRA)
• PRA-tests are used during the diagnostics of hypertension or hypotension

Juxtaglomerular Apparatus

• A structure that sits close to the distal convoluted tubule of the glomerulus
• Macula densa cells are modified epithelial cells of the distal convoluted tubule and the juxtaglomerular cells
• Renin is synthesised in juxtaglomerular cells

Influences on Renin Secretion

• Stimulatory factors:
  • Reduced blood pressure in the afferent arteriole sensed by baroreceptors
  • Reduced NaCl reabsorption by macula densa cells via prostaglandins
  • Increased sympathetic adrenergic activity from renal nerves and catecholamines via β-adrenoreceptors
• Inhibitory factors:
  • Increased NaCl absorption by the macula densa
  • Increased pressure in afferent arteriole
  • Reduced sympathetic activity
  • Angiotensin II via negative feedback

Renin Secretion in detail

• Renin-release is induced by:
  • GsPCRs
  • cAMP
• Renin-release is inhibited by:
  • GqPCRs
  • Ca2+

Conditions Increasing Renin

• Low blood pressure caused by:
  • Sodium depletion and diuretics
  • Hemorrhage and dehydration
  • Heart failure and cirrhosis of the liver
• Fight or flight responses via:
  • Sympathetic nervous system
  • Plasma adrenaline
• Renin inhibitors, e.g. Aliskirin are used clinically to treat high blood pressure

Angiotensin II Origin

• Derived from angiotensinogen
  • Glycoprotein created in liver
  • 453 amino acids long
  • Present in high concetrations
• ACE is primarily in lung endothelial cells

Angiotensin I

• Split from Angiotensinogen by Renin
• It is physiologically inactive

Angiotensin Conversion

– ACE primarily located in endothelial cells in Lung

• ACE is removing His and Leu from the carboxy terminus of Angiotensin I to form Angiotensin II
• Carboxypeptidase enzyme
• Angiotensin II = main effector of RAAS
• ACE inhibitors treat high blood pressure

Peptide Processing of Angiotensin

• Pathway is: Angiotensinogen -> Angiotensin I -> Angiotensin II -> Angiotensin III -> Angiotensin 1-7
• ACE and Renin facilitate these proccesses

Angiotensin II receptors

• AT1R receptors primarily mediate the cardiovascular effects of ANG II
  • AT1A are principally in blood vessels
  • AT1B are in the adrenal cortex and anterior pituitary
• AT2R receptors are more plentiful in the neonate and foetus
• AT1Rs are GPCR that are linked to PLC
• They cause elevations in Ca2+I
• AT1R receptor blockers (ARBs) treat hypertension and cardiac failure by drugs such as candesartan and eprosartan

Biological Activities of Angiotensin II

• Actions through AT1R consists of:
  • Tubular Na reabsorption
  • Vasoconstriction
  • Aldosterone and ADH release
• RAAS is regulated via feedback inhibition

Tubular Sodium Reabsorption

• Angiotensin II stimulates sodum reabsorption in the PCT by activating the AT1 receptors and stimulating
  • NHE across the luminal membrane
  • Na+/K+ ATPase pump on the basolateral membrane
  • Na+/HCO3 co-transport across the basolateral membrane
• Ang II induced increased in sodium absorption drive water reabsorption

Vasoconstriction

• Mediated by AT1 receptors
• This raises overall systemic blood pressure
• Reduces filtration rate and urine production
• Raises peritubular capillaries and increases resorption

Aldosterone

• Aldosterone is synthesized in zona glomerulosa of the Adrenal Cortex, controlled by AT1
• Lacks 17α hydroxylase activity
• Exhibits'Aldosterone synthase' activity
• Structure of Aldosterone:
  • Mineralocorticoid, acting at a Mineralocortocoid receptor
  • T1/2 about 20 minutes
  • Has low plasma levels (0.17nmol/L)
  • Metabolised principally by liver
  • Enhances reabsorption of sodium+ from distal convoluted tubules

Aldosterone Effects

• Aldosterone increases sodium levels, increasing fluid absorption via increases in:
  • ENaC
  • Na/K ATPase

Regulation of Aldosterone

• It is regulated via feedback mechanism

Hyperaldosteronism

• Hyperaldosteronism is when there is too much aldosterone produced by adrenal glands
• Incidence is 5-10% and is linked to hypertension and hypokalaemia
• Primary hyperaldosteronism:
  • Characterized by higher aldosterone levels by higher aldosterone levels
  • Adrenal adenoma or idiopathic adrenal hyperplasia
  • Diagnosed by serum renin and higher serum aldosterone levels
• Secondary hyperaldosteronism:
  • Caused decreases in heart function

Hypoaldosteronism

• Where there is too little aldosterone produced by adrenal glands
• Primary Hypoaldosteronism:
  • Autoimmune destruction of Adrenal gland
  • Defective aldosterone release from the adrenals
  • Causes, urine loss, hypotension, dehydration, and mineral problems
  • Diagnosis of lower serum aldosterone and higher serum renin
• Secondary Hypoaldosteronism:
  • Caused by renal issues
  • Symptoms are as above
  • Diagnosis is via low serum and aldosterone renin
  • There is a treatment for a high salt diet and replacement of mineralocorticoids

Angiotensin II functions

• Stimulating antidiuretic hormone section
• Which is facilitated by At1R
• ADH is AKA. Argenine Vasopressin - AVP
• Peptide Hormone produced in the pituitary gland (9aa long)
• T1/2 approximately 20minutes
• Increasing water absorption via AVP2R, or vasoconstriction via AVP1R

Anti-Diuretic Hormone

• Increases water absorption in collecting ducts
• Mediated by increased luminal expression of Aquaporin 2
• It promotes expression of urea transporters

Clinical Relevance

• RAAS controls blood volume and arteriolar tone in the short and long-term
• Inappropriate activation leads to hypertension
• RAAS can be targeted for drugs, can assist with:
  • management of heart failure, hypertension, myocardial infarction
• Drugs used include ACE inhibitors, angiotensin receptor blockers , aldosterone antagonists, direct renin inhibitors which: lower solution concentrations and reabsorbtion rates in vessels
• RAAS modulators are used in the management of diabetes mellitus by managing glucose and BP
• Used to treat diabetic nephropathy