Renal Physiology Notes

Course Information

• Course Title: Renal Physiology
• Date: 2/5/26
• Institution: SCHOOL OF MEDICINE, UNC Cell Biology and Physiology
• Instructor: Emily Moorefield, PhD
• Contact: emily_moorefield@med.unc.edu

Learning Objectives

• Reabsorption Mechanisms: Describe how sodium and water are reabsorbed from the nephron segments.
• Hormonal Regulation: Describe the major hormones that are essential for sodium and water homeostasis (angiotensin II, aldosterone, antidiuretic hormone, and atrial natriuretic peptide).
• Urine Concentration Mechanisms: Describe how dilute and concentrated urine are created.
• Clinical Aspects of ADH: Define and describe the regulation, secretion, and action of antidiuretic hormone (ADH) in the kidney.

Nephron Function by Segment

• Bowman's Capsule:
  • Function: Filtration of plasma into Bowman’s space.
• Proximal Tubule:
  • Reabsorption Rates:
  • 60-70% of Na⁺ and water.
  • All glucose and amino acids.
  • Most bicarbonate and K⁺.
• Loop of Henle:
  • Responsible for creating a hyperosmotic medullary interstitium, crucial for concentrating urine.
  • Further reabsorption of Na⁺, resulting in additional dilution of forming urine.
• Late Distal Tubule/Collecting Duct:
  • Involved in fine-tuning Na⁺ and water reabsorption, regulated by hormones.

Late Distal Tubule/Collecting Duct Details

• Cell Types:
  • Principal Cells:
  • $ext{H}_2 ext{O}$ reabsorption, Na⁺ reabsorption, K⁺ secretion.
  • α-Intercalated Cells:
  • H⁺ secretion, HCO₃^- reabsorption.
• Key Transport Mechanisms:
  • Use of Na⁺ /K⁺ ATPase and epithelial Na⁺ channels (ENaC).
  • K⁺ secretion facilitated by ROMK channels.
  • Water is reabsorbed via aquaporin (AQP) channels under the influence of ADH.
• Osmolarity Range:
  • Tubular fluid reaches an osmolarity of 80 mOsm/L to 1200 mOsm/L depending on ADH presence.

Sodium Handling in the Nephron

• Proximal Tubule:
  • Reabsorption alongside amino acids, glucose, and Cl^-.
• Thick Ascending Limb:
  • Utilizes NKCC cotransporter.
• Early Distal Tubule:
  • Utilizes NCC cotransporter.
• Late Distal Tubule/Collecting Duct:
  • Uses ENaC channels for Na⁺ reabsorption.

Mechanisms Regulating Sodium Balance

• Renin-Angiotensin-Aldosterone System (RAAS):
  • Activates in response to extracellular volume contraction.
  • Angiotensin II (Ang II) constricts efferent arterioles, increasing GFR.
  • Ang II stimulates Na⁺ reabsorption in the proximal tubule.
  • Aldosterone promotes Na⁺ reabsorption and K⁺ secretion in the distal nephron.
• Sympathetic Nervous Activity:
  • Responds to extracellular volume contraction and constricts afferent arterioles, decreasing NaCl delivery to macula densa.
• Atrial Natriuretic Peptide (ANP):
  • Secreted in response to extracellular volume expansion.
  • Dilation of afferent arterioles increases GFR; decreases renin, Ang II, and aldosterone release.

Special Anatomy: The Juxtaglomerular Apparatus

• Structure: Formed by specialized cells of the afferent arteriole and distal tubule.
• Function: A key regulator for the renin-angiotensin-aldosterone system (RAAS).

Renin Release Mechanism

• Trigger Factors for Renin Release:
  • ↓ Blood Pressure (sensed by Juxtaglomerular (JG) cells).
  • ↓ NaCl delivery (sensed by macula densa).
  • ↑ Sympathetic stimulation affecting JG cells.
• Response to Volume Contraction:
  • JG cells release renin, responding to reduced stretch and sympathetic signaling, leading to Ang II production.

Renin-Angiotensin-Aldosterone System (RAAS) Pathway

• Sequence:
  • Renin catalyzes conversion of angiotensinogen to angiotensin I.
  • Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE).
  • Angiotensin II leads to aldosterone secretion from the zona glomerulosa of adrenal glands.
  • Aldosterone enhances Na⁺ reabsorption and K⁺ secretion in nephron regions.

Action of Angiotensin II

• Key functions include:
  • Maintaining renal perfusion through efferent arteriole constriction.
  • Activating Na⁺/H⁺ exchanger to enhance sodium reabsorption.
  • Stimulating aldosterone release to act on the distal nephron.

Aldosterone Function

• Type: Steroid hormone that binds to intracellular mineralocorticoid receptors.
• Mechanism:
  • Translocates to nucleus to influence transcription as a transcription factor.
  • Promotes synthesis of ENaC channels and Na^+/K+ ATPase.
  • Increases ATP production within mitochondria.

Effects of ENaC Mutations

• Gain-of-Function Mutation in ENaC:

  • Activity: Very high.
  • Na⁺ Handling: Excess Na⁺ reabsorption.
  • Volume Status: Extracellular volume (ECV) expansion.
  • K⁺ Balance: Hypokalemia.
  • Aldosterone Levels: Low (suppressed).

• Loss-of-Function Mutation in ENaC:

  • Activity: Minimal or absent.
  • Na⁺ Handling: Excess Na⁺ excretion.
  • Volume Status: ECV contraction.
  • K⁺ Balance: Hyperkalemia.
  • Aldosterone Levels: High (compensatory).

Atrial Natriuretic Peptide (ANP)

• Stimulus: Released in response to ↑ blood volume/stretch.
• Mechanism:
  • Dilates afferent arterioles and increases GFR.
  • Decreases aldosterone, reducing Na⁺ reabsorption.
• Effects:
  • Enhances Na⁺ excretion.
  • Counteracts RAAS effects.

Water Balance in the Kidneys

• Fluid Excess Response: Excretion of large volumes of dilute urine (as low as 50 mOsm).
• Fluid Limitation Response: Excretion of small volumes of concentrated urine (as high as 1200 mOsm).

Actions of Antidiuretic Hormone (ADH)

• Stimuli for Release:
  • Increased plasma osmolarity, small changes in which adjust ADH levels.
  • Decreased blood volume, requiring large changes to modify ADH levels.
• Mechanism:
  • Binds to V2 receptors on the late distal tubule/collecting duct, increasing permeability and facilitating water reabsorption via AQP channels.
• Feedback System:
  • Maintains constant water levels; loss of water leads to rise in serum osmolarity, prompting thirst and ADH release.

Impact of ADH on Urine Properties

• Functions of ADH:
  • Stabilizes urine solute while varying urine water content.
  • Higher ADH results in smaller urine volume with stable solute excretion.
  • Lower ADH leads to larger urine volume at identical solute excretion levels.

Water Reabsorption Dynamics

• Tubular Fluid Characteristics: Variable osmolarity in the late distal tubule and collecting duct.
• Water reabsorption relies on AQP2 presence regulated by ADH.

Absence of ADH Effects

• Consequences:
  • No permeability to water in late distal tubule/collecting duct.
  • Results in large volume dilute urine excretion (up to 22 liters as extreme example).

Presence of ADH Effects

• Consequences:
  • Increases urine osmolarity to approximately 1200 mOsm and reduces volume.

Disorders Related to ADH

• Syndrome of Inappropriate ADH Release (SIADH):
  • Autonomously secreted ADH, potentially due to tumors or drugs.
• Central Diabetes Insipidus:
  • Impaired ADH secretion due to head injury or autoimmune conditions.
• Nephrogenic Diabetes Insipidus:
  • V2 receptor insensitivity to ADH, potentially caused by medications or chronic kidney conditions.

Summary of Serum and Urine Changes in Response to Fluid States

• Water Deprivation Impact:
  • ↑ ADH, high-normal plasma osmolarity, hyperosmotic urine, low urine flow rate.
• Water Drinking Impact:
  • ↓ ADH, low-normal plasma osmolarity, hyposmotic urine, high urine flow rate.
• SIADH Allocation:
  • ↑↑ ADH, low plasma osmolarity, hyperosmotic urine, low urine flow rate.
• Effect of Central Diabetes Insipidus:
  • ↓↓ ADH, high plasma osmolarity, hyposmotic urine, high urine flow.
• Effect of Nephrogenic Diabetes Insipidus:
  • ↑ ADH (compensatory), high plasma osmolarity, hyposmotic urine, high urine flow rate.

Responses to Extracellular Volume Changes

• Expansion:
  • ↑ Renal perfusion pressure leads to NaCl delivery to macula densa, resulting in ANP secretion and adjustment to increase GFR and H2O reabsorption by distal structures.
• Contraction:
  • Decreased renal perfusion pressure, undergoes responses through JG cells, sympathetic activity, renal adjustments leading to altered Na⁺ reabsorption by collecting ducts.