Lecture 1: Introduction to Epithelial Cells

Where Epithelial Cells Are Found

Epithelia line anywhere the internal environment meets the external environment.

Major locations

• Skin

• Digestive tract (lumen = external environment)

• Respiratory tract (air = external)

• Urinary tract

• Reproductive tract

• Secretory glands (mammary, salivary, sweat)

Core idea

Functions of Epithelial Tissues

A. Protection (primary function)

Protects from:

• UV radiation

• Mechanical damage

• Pathogens

• Digestive enzymes

• Toxins

• Dust, allergens, chemicals

Mechanisms:

• Tight junctions seal the barrier

• Multiple layers (stratified epithelia) resist abrasion

• Mucus secretion traps pathogens

• Antimicrobial peptides (Paneth cells)

B. Transport

Epithelia regulate movement of:

• ions

• water

• metabolites

Transport occurs through cells (transcellular) or between cells (paracellular, controlled by tight junctions).

C. Absorption

Epithelial cells absorb nutrients from the external environment → pass to bloodstream.

Examples:

• Intestinal epithelium (microvilli ↑ surface area)

• Renal tubules (reabsorption)

D. Sensing

Specialised epithelial cells detect:

• chemicals (olfaction)

• mechanical stimuli

• irritants

E. Secretion

Epithelial cells secrete:

• mucus (goblet cells)

• antimicrobial peptides (Paneth cells)

• milk (mammary glands)

• oils (sebaceous glands)

Three secretion types

1. Merocrine — vesicles fuse with membrane; cell remains intact

   • e.g., Paneth cells

2. Apocrine — apical portion of cell pinches off

   • e.g., mammary glands

3. Holocrine — whole cell dies and becomes secretion

   • e.g., sebaceous glands

Characteristics of Epithelial Tissues

A. High cellularity

• Densely packed cells

• Minimal extracellular matrix

• Forms continuous sheets

B. Polarity

Each epithelial cell has three domains:

1. Apical — faces external environment

   • may have microvilli, cilia, secretory specialisations

2. Lateral — faces neighbouring cells

   • contains junctions

3. Basal — faces internal environment

   • attaches to basement membrane

C. Attachment

Two categories:

1. Cell‑to‑cell junctions

Always arranged apical → basal in this order:

1. Tight junctions

   • Seal the top of the epithelium

   • Size‑selective barrier

   • Key proteins: claudins, occludin, JAM, ZO proteins

   • Claudin type determines “tight vs leaky” epithelium

2. Adherens junctions

   • Sense & transmit mechanical tension

   • First junctions to form

   • Key proteins: E‑cadherin, β‑catenin, α‑catenin (mechanosensitive), actin

   • Calcium‑dependent

3. Desmosomes

   • Strong mechanical adhesion

   • Link to intermediate filaments

   • Key proteins: desmoglein, desmocollin, plakoglobin, plakophilin

4. Gap junctions

   • Channels for ions/metabolites

   • Made of connexins

2. Cell‑to‑matrix junctions

Located at the basal side:

1. Hemidesmosomes

   • Anchor cells to basement membrane

   • Use integrins

   • Link to intermediate filaments

2. Focal adhesions

   • Integrin‑based

   • Link to actin

   • Dynamic; signalling hubs; allow cell migration

D. Avascularity

• No direct blood supply

• Nutrients diffuse from underlying connective tissue

• Basement membrane always separates epithelium from blood vessels

E. Hyper‑regeneration

• Epithelia regenerate rapidly

• Essential due to constant exposure to damage

• Stem cells usually located in basal layer (stratified epithelia)

🧱 4. Classification of Epithelia

A. By cell shape

• Squamous — flat

• Cuboidal — cube‑shaped

• Columnar — tall

B. By number of layers

1. Simple (one layer)

• All cells touch basement membrane

• Nuclei aligned at same height

Functions: absorption, secretion, gas exchange

Examples:

• Simple squamous → alveoli, blood vessels

• Simple cuboidal → kidney tubules, thyroid

• Simple columnar → intestine (microvilli), lung (ciliated)

2. Stratified (multiple layers)

• Only basal layer touches basement membrane

• Top layer defines classification

Functions: protection

Examples:

• Stratified squamous → skin, oesophagus

• Stratified cuboidal → sweat/salivary gland ducts

• Stratified columnar → mammary glands, urethra

3. Pseudostratified

• Appears multilayered (nuclei at different heights)

• But every cell touches basement membrane

• Common in airways

• Often ciliated + goblet cells

Function: mucus secretion + movement

4. Transitional

• Found in urinary bladder

• Shape changes depending on stretch

• Relaxed → tall, rounded cells

• Stretched → flattened cells

Function: organ expansion

Functional Summary of Epithelial Types

Exam‑Ready Key Points (Kinga’s “KEY” slides)

• Epithelia = barrier between internal & external environments

• Functions: protection, transport, absorption, sensing, secretion

• Characteristics: high cellularity, polarity, attachment, avascularity, regeneration

• Six junction types: tight, adherens, desmosomes, gap junctions, hemidesmosomes, focal adhesions

• Tight junctions ALWAYS at apical side

• Adherens junctions form first + sense tension

• Desmosomes = strong mechanical adhesion

• Gap junctions = communication

• Hemidesmosomes = basal anchoring

• Focal adhesions = signalling + migration

• Classification by shape and layers

• Transitional epithelium = bladder stretch adaptation

Lecture 2: EPITHELIAL TRANSPORT

Two Major Routes of Transepithelial Transport

A. Paracellular Transport

• Solutes move between epithelial cells.

• Must pass through tight junctions.

• Controlled by claudin composition.

• Only small ions + water can pass (depending on tightness).

• No transporters involved.

Key concept:

B. Transcellular Transport

• Solutes move through the cell.

• Must cross apical membrane → cytosol → basolateral membrane.

• Requires channels, carriers, pumps.

Two types:

1. Passive transport (no energy)

2. Active transport (requires energy)

🧬 2. Tight Junctions in Transport

Main function:

Key proteins:

• Claudins (>20 types) → determine pore size

• Occludin

• JAM

• ZO proteins (link to actin)

Tight vs Leaky Epithelium

• Tight epithelium

  • Very restrictive

  • Minimal paracellular flow

  • Example: distal nephron, stomach

• Leaky epithelium

  • Allows water + small ions to pass

  • Example: proximal tubule, small intestine

Claudin pore sizes

• Tight claudins: ~0.3 nm

• Leaky claudins: ~1 nm

• Compare sizes:

  • Na⁺ = 0.19 nm

  • K⁺ = 0.235 nm

  • Water = 0.4 nm

  • Glucose = 4 nm (too large → must be transcellular)

Passive Transcellular Transport

General rules

• No ATP required

• Moves down concentration or electrochemical gradient

• Includes:

  • Simple diffusion

  • Facilitated diffusion (channels + carriers)

A. Simple Diffusion

• Only small, uncharged, lipid‑soluble molecules:

  • O₂

  • CO₂

  • small lipids

• No protein required.

B. Facilitated Diffusion

Used for:

• Charged ions

• Large molecules (e.g., glucose)

• Water (via aquaporins)

Two mechanisms:

1. Channel‑mediated

   • Ion channels

   • Aquaporins (water only)

2. Carrier‑mediated

   • GLUT transporters (glucose)

   • Amino acid carriers

Electrochemical gradient

For charged molecules, movement depends on:

• Concentration gradient

• Membrane potential

Active Transcellular Transport

General rules

• Requires energy

• Moves solutes against their gradient

• Two types:

  1. Primary active transport (direct ATP use)

  2. Secondary active transport (uses gradient of another ion)

A. Primary Active Transport

Na⁺/K⁺ ATPase (the pump)

• Located on basolateral membrane

• Pumps:

  • 3 Na⁺ OUT

  • 2 K⁺ IN

• Uses ATP hydrolysis

• Maintains:

  • Low intracellular Na⁺

  • High intracellular K⁺

  • Negative membrane potential

Importance

B. Secondary Active Transport

Uses energy stored in Na⁺ gradient.

Example: SGLT (Sodium‑Glucose Cotransporter)

SGLT1

• 2 Na⁺ : 1 glucose

• Location: small intestine, S3 kidney segment

• High‑affinity transporter

SGLT2

• 1 Na⁺ : 1 glucose

• Location: S1/S2 kidney proximal tubule

• Low‑affinity, high‑capacity

Mechanism

• Na⁺ moves down its gradient (into cell)

• Glucose is dragged against its gradient

• Glucose exits basolateral side via GLUT2 (facilitated diffusion)

Key concept:

🧱 5. Putting It All Together — Intestinal Glucose Absorption

Apical membrane

• SGLT1 brings in Na⁺ + glucose (secondary active transport)

Basolateral membrane

• Na⁺/K⁺ ATPase pumps Na⁺ out (primary active transport)

• GLUT2 transports glucose into bloodstream (facilitated diffusion)

Outcome

Efficient glucose absorption from lumen → blood.

⭐ 6. Exam‑Ready Key Points (Kinga’s “KEY” Slides)

• Two transport routes: paracellular vs transcellular

• Tight junctions determine tight vs leaky epithelia

• Claudins = pore‑forming proteins controlling paracellular permeability

• Passive transport = down gradient, no ATP

• Active transport = against gradient, requires ATP or Na⁺ gradient

• Na⁺/K⁺ ATPase = essential for maintaining gradients

• SGLT = secondary active transport of glucose

• GLUT = facilitated diffusion of glucose out of cell

Lecture 3: RESPIRATORY EPITHELIUM

Overview of the Respiratory Epithelium

The respiratory tract is divided into:

A. Conducting Zone

Nasal cavity → trachea → bronchi

• Function: conduct air into lungs

• Epithelium: pseudostratified columnar

  • All cells touch basement membrane

  • Different heights → nuclei at different levels

B. Respiratory Zone

Alveoli

• Function: gas exchange

• Epithelium: simple squamous

  • Very thin for diffusion

  • Two specialised cell types: AT1 and AT2

🧬 2. Cell Types in the Conducting Epithelium

A. Ciliated Cells

• ~50% of airway epithelial cells

• Hundreds of motile cilia per cell

• Cilia beat in coordinated waves to move mucus towards oesophagus

• Require:

  • Dynein arms (ATP‑powered motor proteins)

  • 9+2 microtubule arrangement

Ciliary dysfunction

• Primary ciliary dyskinesia (PCD)

  • Genetic mutations → immotile/abnormal cilia

  • Mucus cannot be cleared → chronic infections

• COPD / smoking / pollutants

  • Cilia become shorter, slower

  • Goblet cell hyperplasia replaces ciliated cells

B. Goblet Cells

• Merocrine secretion of mucus

• Mucus composition:

  • MUC5B (baseline)

  • MUC5AC (upregulated in infection/allergy → thicker, stickier)

  • Water, lipids, antibodies, salts, debris

Functions

• Trap pathogens, allergens, dust

• Hydrate and lubricate airway surface

C. Basal Cells (Airway Stem Cells)

• Small cells located at basement membrane

• Stem/progenitor cells of conducting epithelium

• Normally quiescent

• Activated by:

  • Tissue injury

  • Mechanical tension changes sensed via adherens junctions

Differentiation pathways

Basal cell →

• Club cell → goblet cell

• Deuterosomal cell → ciliated cell

• Minor cell types (ionocytes, tuft cells, NECs)

RSV infection

• RSV infects basal cells → forces differentiation into goblet cells

• Leads to goblet cell hyperplasia → excessive mucus → chesty cough

D. Minor Cell Populations

1. Club (Clara) Cells

• Secrete CCSP (anti‑inflammatory)

• “Second stem cells” — can regenerate goblet + ciliated cells

2. Neuroendocrine Cells (NECs)

• Innervated by neurons

• Release neuropeptides → regulate breathing rate

3. Tuft Cells

• Chemosensory cells

• Detect harmful bacteria/allergens

• Release cytokines → activate immune responses

4. Ionocytes

• High expression of ion channels (including CFTR)

• Regulate airway pH and hydration

5. Deuterosomal Cells

• Pre‑ciliated cells

• Use energy to generate hundreds of cilia

🌬 3. Airway Surface Liquid (ASL)

ASL = two layers:

1. Periciliary sol layer (watery)

   • Cilia beat within this layer

   • Maintained by CFTR chloride channels + aquaporins

2. Mucus layer

   • Floats on top

   • Moved by ciliary motion

Mechanism

• CFTR pumps Cl⁻ out → water follows via aquaporins → maintains hydration

• Essential for mucus clearance

🫁 4. Alveolar Epithelium (Respiratory Zone)

A. AT1 Cells (Alveolar Type I)

• Simple squamous

• Extremely thin

• Cover ~95% of alveolar surface

• Function: gas exchange

Gas exchange mechanism

• Passive diffusion (no energy)

• O₂: alveolus → blood

• CO₂: blood → alveolus

• Driven by concentration gradients

B. AT2 Cells (Alveolar Type II)

• Cuboidal

• Functions:

  1. Produce surfactant (SP‑C)

     • Reduces surface tension

     • Prevents alveolar collapse

  2. Progenitor cells

     • Replace damaged AT1 and AT2 cells

     • Respond to tension changes via adherens junctions

🫧 5. Surfactant & Alveolar Stability (Law of Laplace)

Pressure = 2 × Surface Tension / Radius

Without surfactant:

• Small alveoli → high pressure → collapse

• Air shifts into larger alveoli

With surfactant:

• Small alveoli secrete more surfactant

• Surface tension reduced more

• Pressure equalised across alveoli of different sizes

• Prevents collapse → efficient gas exchange

⚠ 6. Respiratory Disorders

A. Cystic Fibrosis

• Mutation in CFTR chloride channel

• Consequences:

  • No Cl⁻ secretion → no water movement

  • Dehydrated ASL

  • Thick, sticky mucus

  • Impaired clearance → chronic infection + inflammation

CFTR mutation classes

1. No protein (nonsense mutation)

2. Misfolded protein (ER degradation)

3. Defective gating

4. Reduced conductance

5. Reduced protein synthesis

6. Unstable protein

Classes I–III = severe

Classes IV–VI = milder

B. Allergies (e.g., house dust mite)

• Allergen proteases cleave tight junction proteins (claudins, occludin)

• Barrier breaks → allergens enter tissue

• Epithelial cells release IL‑33, IL‑25, TSLP

• Activates:

  • ILC2

  • Th2 cells

  • B cells → IgE

  • Mast cells, eosinophils, basophils

• Leads to inflammation + mucus overproduction

C. Asthma

• Features:

  • Goblet cell hyperplasia

  • Excessive MUC5AC production

  • Thickened basement membrane

  • Loss of tight junctions + adherens junctions

  • Airway narrowing + mucus plugging

⭐ 7. High‑Yield Exam Points

• Conducting zone = pseudostratified; respiratory zone = simple squamous

• Cilia = 9+2 microtubules + dynein

• Goblet cells: MUC5B baseline, MUC5AC in disease

• Basal cells = stem cells; activated by tension

• ASL requires CFTR + aquaporins

• AT1 = gas exchange; AT2 = surfactant + progenitor

• Surfactant prevents collapse of small alveoli

• CF = dehydrated mucus due to CFTR failure

• Allergens cleave tight junctions → Th2 response

• Asthma = mucus hypersecretion + epithelial damage

Lecture 4: Intestinal epithelium

1. Overview of GI tract & epithelial organisation

• GI tract: mouth → pharynx → oesophagus → stomach → small intestine → large intestine → rectum → anus.

• Digestion begins in oral cavity (salivary α‑amylase).

• Stomach: HCl denatures proteins, activates pepsin, sterilises food.

• Small intestine receives bile (liver/gallbladder) + digestive enzymes (pancreas) → major site of digestion & absorption.

• 90% of water absorbed in small intestine; remaining 10% in large intestine.

• Both small & large intestine lined by simple columnar epithelium.

2. Small vs Large Intestine

Small intestine

• Villi present → massive surface area for nutrient absorption.

• Villi contain blood vessels + lacteals in the core.

• Crypts present.

Large intestine

• No villi, flat surface.

• Crypts still present.

• Main function: water reabsorption, formation of stool.

• Heavy bacterial colonisation.

3. Histology orientation

• Epithelial cells = the single layer directly touching the lumen.

• Beneath epithelium: connective tissue, immune cells, fibroblasts, smooth muscle, blood vessels.

• Villi = protrusions; crypts = invaginations.

4. Intestinal Epithelial Cell Types

Five major cell types

1. Intestinal stem cells

2. Paneth cells

3. Goblet cells

4. Enteroendocrine cells

5. Enterocytes

5. Intestinal Stem Cells

• Located at base of crypts.

• Multipotent, continuously self‑renewing.

• Divide → transit‑amplifying cells → differentiate as they migrate up villus.

• Entire intestinal epithelium replaced every ~4 days.

BRDU evidence

• BRDU = thymidine analogue incorporated during DNA replication.

• After 48 hrs, labelled cells migrate ~40% up the villus → confirms rapid turnover.

• “Anything with this very dark staining are the BRDU‑positive cells.” (from transcript)

6. Paneth Cells

• Found only in crypts, interspersed with stem cells.

• Contain large secretory granules (defensins, lysozyme, phospholipase A2).

• Two key roles:

  1. Antimicrobial defence (merocrine secretion into lumen).

  2. Maintain stem cell niche via:

     • Wnt → “stay a stem cell” (self‑renewal, multipotency).

     • EGF / TGF‑α → “keep dividing” (proliferation).

     • Delta‑like ligands → Notch → “do not differentiate”.

Loss of Paneth cells → loss of antimicrobial defence + collapse of stem cell maintenance.

7. Goblet Cells

• Produce mucus (dominant mucin = MUC2 in gut).

• Mucus functions:

  • Physical barrier preventing bacterial contact with epithelium.

  • Lubrication.

  • Hydration of epithelial surface.

• Mucin composition varies with:

  • Region (small vs large intestine)

  • Microbiota

  • Immune signalling (e.g., flagellin ↑ MUC5A)

  • Diet (fibre ↑ mucin production)

Mucus layers

Small intestine

• Single, loose mucus layer

• Almost sterile (Paneth antimicrobial peptides + high flow + digestive enzymes).

• Constantly diluted by water absorption.

Large intestine

• Two layers:

  • Inner layer: dense, sterile, attached to epithelium.

  • Outer layer: loose, heavily colonised by commensal bacteria.

Mutualism

• Bacteria get: warm environment, water, mucin sugars, undigested fibre.

• Host gets:

  • Vitamins (K, B‑group)

  • Short‑chain fatty acids (e.g., butyrate → major fuel for colonocytes)

  • Protection via competitive exclusion of pathogens.

8. Enteroendocrine Cells

• Secrete hormones basally (towards bloodstream).

• Regulate digestion, appetite, and motility.

Key hormones

• Gastrin → ↑ acid

• CCK → ↑ bile + pancreatic enzymes; satiety

• Secretin → ↑ bicarbonate

• Ghrelin → hunger

• GLP‑1 → satiety + insulin release

• Motilin → MMC between meals

• VIP → relaxation

• Somatostatin → inhibition

9. Enterocytes

• 80–95% of intestinal epithelial cells.

• Tall columnar cells with dense microvilli (“brush border”).

• Primary role: absorption of nutrients.

Microvilli

• 200–1000 per enterocyte.

• Actin‑based, static structures.

• Stabilised by villin, fimbrin, espin.

• Anchored by myosin‑6, myosin‑7b, ezrin.

• Increase membrane surface → more transporters → more absorption.

Microvilli vs Cilia

• Microvilli: actin core, non‑motile.

• Cilia: 9+2 microtubules, motile (airway).

• “Which structure moves? Cilia.” (from transcript)

10. Glucose Absorption Mechanism

Basolateral Na⁺/K⁺ ATPase

• Pumps 3 Na⁺ out / 2 K⁺ in.

• Creates low intracellular Na⁺ → driving force for glucose uptake.

Apical SGLT1

• Symporter: 2 Na⁺ + 1 glucose into cell.

• Secondary active transport (depends on Na⁺ gradient).

Basolateral GLUT2

• Uniporter, passive.

• Moves glucose into bloodstream.

11. Epithelial Cell Extrusion

• Occurs at tip of villus.

• Maintains homeostasis: cell birth = cell death.

• Neighbouring cells extend beneath the dying/extruding cell → re‑establish adherens junctions.

Two possible mechanisms

1. Apoptotic extrusion

   • Cell undergoes apoptosis → neighbours detect → squeeze out.

2. Live‑cell extrusion

   • Overcrowding → viable cell pushed out → loses junctions → undergoes anoikis.

Failure of extrusion or excessive proliferation → polyps → adenoma → carcinoma.

12. Celiac Disease

• Gluten triggers T‑cell mediated inflammation.

• Inflammatory mediators ↑ epithelial cell death.

• Death > proliferation → villus atrophy, reduced absorption → malnutrition.

13. Common Exam Traps

• Villi ≠ microvilli

  • Villi = tissue‑level protrusions with blood vessels.

  • Microvilli = actin‑based projections on enterocytes.

• Paneth cells are NOT goblet cells

  • Paneth = antimicrobial + stem cell niche.

  • Goblet = mucus.

• Enteroendocrine cells secrete basally, not into lumen.

• Small intestine mucus is sterile, large intestine outer mucus is colonised.

Lecture 5: Renal Epithelium

1. Overview of the Renal System

• Components: kidneys → ureters → bladder → urethra.

• Kidneys filter blood, reclaim essential solutes/water, and produce urine.

• Urine drains via ureter → stored in bladder → exits via urethra.

2. Nephron Structure & Kidney Regions

Nephron = functional filtration + reabsorption unit

• Blood enters via afferent arteriole, forms glomerulus (capillary tuft).

• Filtrate enters Bowman’s capsule, then flows through:

  1. Proximal tubule

  2. Loop of Henle (descending → ascending)

  3. Distal tubule

  4. Collecting duct

Cortex vs Medulla

• Cortex (~300 mOsm/L)

  • Contains glomeruli, proximal & distal tubules.

  • Site of filtration + most reabsorption.

• Medulla (up to ~1200 mOsm/L)

  • Contains loops of Henle + collecting ducts.

  • High osmolarity drives water reabsorption.

3. Epithelial Types Along the Nephron

4. Renal Epithelial Regeneration

• Unlike intestine/airways, no resident stem cell niche.

• Kidneys rarely face infection → low turnover.

• After injury:

  1. Dedifferentiation → cells revert to stem‑like state

  2. Proliferation

  3. Redifferentiation into required epithelial type

• Markers during dedifferentiation: CD24+, CD44+, CD133+, SOX9+, vimentin+, PAX2+.

5. Juxtaglomerular Apparatus (JGA)

Macula densa (distal tubule)

• Senses NaCl concentration in filtrate.

• Low NaCl = low GFR = interpreted as low blood pressure.

Juxtaglomerular (JG) cells

• Modified smooth muscle cells of afferent arteriole.

• Release renin when macula densa detects low NaCl.

• Renin → RAAS activation → ↑ Na⁺ retention + ↑ water retention → ↑ blood pressure.

6. Glomerular Filtration

Podocytes

• Specialised epithelial cells with primary processes + foot processes.

• Foot processes interlock to form slit diaphragm (nephrin‑based).

• Size‑selective barrier: excludes molecules > ~9 nm (e.g., albumin, antibodies, blood cells).

Filtration forces

• HPg (glomerular hydrostatic pressure) = 55 mmHg (pushes filtrate out).

• OPg (oncotic pressure) = 30 mmHg (pulls water back in).

• HPc (capsular hydrostatic pressure) = 15 mmHg (pushes back).

Net Filtration Pressure (NFP)

[ \text{NFP} = 55 - (30 + 15) = 10 \text{ mmHg} ]

7. Reabsorption of Glucose

Transporters

• SGLT2 (early proximal tubule):

  • Fast, high‑capacity.

  • 1 Na⁺ : 1 glucose.

  • Reabsorbs >90% of filtered glucose.

• SGLT1 (late proximal tubule):

  • Slower, high‑affinity.

  • 2 Na⁺ : 1 glucose.

  • Reabsorbs remaining <10%.

Basolateral GLUT2

• Passive uniporter → returns glucose to bloodstream.

Clinical relevance

• SGLT2 inhibitors (diabetes treatment):

  • Block SGLT2 → ~50% of glucose excreted → ↓ blood glucose.

  • SGLT1 remains active → prevents hypoglycaemia + preserves intestinal glucose absorption.

8. Reabsorption of Ions

Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2)

• Located in ascending limb.

• Secondary active transport driven by Na⁺ gradient created by Na⁺/K⁺ ATPase.

• K⁺ recycled to allow continuous function.

• Cl⁻ exits basolaterally via Cl⁻ channels.

Why chloride matters:

• Required for HCl production in stomach.

• Required for CFTR‑mediated mucus hydration in airways.

9. Water Reabsorption

Daily: ~180 L filtrate → ~1–2 L urine

→ kidneys must reabsorb ~99% of water.

Proximal tubule (60–70%)

• Leaky tight junctions → paracellular water flow.

• Aquaporin‑1 on apical + basolateral membranes → transcellular flow.

Descending limb of Loop of Henle (20–30%)

• Permeable to water (AQP1).

• Moves into increasingly hyperosmotic medulla (300 → 1200 mOsm/L).

• Water leaves until filtrate osmolarity matches medulla.

Ascending limb

• Impermeable to water (tight junctions + no aquaporins).

• Actively reabsorbs NaCl → lowers filtrate osmolarity to ~100 mOsm/L.

Distal tubule

• Filtrate enters at ~100 mOsm/L.

• Cortex osmolarity = 300 mOsm/L → water reabsorbed until filtrate reaches ~300.

Collecting duct (final regulation)

• Controlled by AVP (vasopressin):

  • AVP → AQP2 inserted into apical membrane.

  • Water exits via AQP3/4 basolaterally.

• Urea reabsorption (UT‑A1, UT‑A3) also AVP‑dependent → maintains medullary osmolarity.

Hydration states

• High AVP → concentrated urine (dehydration).

• Low AVP → dilute urine (overhydration).

10. Urothelium (Ureter + Bladder)

Transitional epithelium

• Highly stretchable.

• Protects from toxic, hyperosmotic urine.

• One of the tightest epithelial barriers in the body.

Layers:

1. Basal cells – regeneration + anchoring.

2. Intermediate cells – stratified support.

3. Umbrella cells – apical, urine‑contacting, extremely tight junctions.

11. Key Exam Distinctions

• Descending limb = water‑permeable; ascending limb = water‑impermeable.

• SGLT2 = fast, early; SGLT1 = slow, late.

• Podocytes use slit diaphragms, not tight junctions.

• Proximal tubule = leaky epithelium; rest of nephron = tight.

• Urothelium ≠ simple epithelium → it is transitional.

Lecture 6: Epithelia Revision Notes (Semi‑Condensed, Mechanistic, Exam‑Ready)

⭐ 1. Core Characteristics of Epithelia

High cellularity

Cells tightly packed; minimal ECM.

Polarity

Apical vs basal specialisation (cilia, microvilli, secretion).

Attachment

Cell–cell: tight junctions, adherens junctions, desmosomes, gap junctions

Cell–matrix: hemidesmosomes, focal adhesions.

Avascularity

Separated from blood by basement membrane.

Hyper‑regeneration

Stem cells divide rapidly; differentiated cells short‑lived.

⭐ 2. Adherens Junctions (AJs)

The most dynamic junction + first to form.

Structure

• E‑cadherin (Ca²⁺‑dependent) binds across cells

• Intracellular: β‑catenin → α‑catenin → actin

Mechano sensing

Low tension:

• α‑catenin folded → vinculin site hidden → minimal actin

High tension:

• α‑catenin unfolds → vinculin binds → recruits more actin

• Reinforces cortex → prevents membrane rupture

Physiological relevance

• Transitional epithelia (bladder)

• Alveoli during breathing

• Prevents overstretching → prevents rupture

Apoptotic extrusion

• Apoptotic cells contract strongly → high tension at AJs

• Neighbouring cells assemble actomyosin ring → squeeze cell out

Homeostatic sensing

• Overcrowding → pushing force → extrusion

• Undercrowding → pulling force → stem cell proliferation

⭐ 3. Stem Cells & Cancer Risk

Location

Stem cells are buried deep to protect from mutagens:

• Skin: basal layer

• Intestine: crypt base

• Airways: basal cells under tall pseudostratified cells

Why mutations in stem cells are dangerous

• Stem cells self‑renew → mutation propagates to all daughters

• Differentiated cells are short‑lived → mutations leave body quickly

Why 80–90% of cancers are epithelial

1. Direct exposure to mutagens (UVB, smoke, alcohol metabolites, bacterial toxins)

2. High proliferation → less time for DNA repair

⭐ 4. Specialised Epithelial Cells

Respiratory Epithelium (Conducting Zone)

• Ciliated cells – microtubule‑based cilia, ATP‑driven mucus clearance

• Goblet cells – mucin 5B (healthy), mucin 5AC (infection)

• Club cells – anti‑inflammatory CCSP

• Neuroendocrine cells – regulate breathing

• Tuft cells – detect pathogens, release cytokines

• Basal cells – stem cells (activated only when damaged)

Intestinal Epithelium

• Stem cells – constantly active; located in crypts

• Paneth cells – antimicrobial peptides + maintain stem cells (Wnt, EGF, Notch)

• Goblet cells – mucin 2 (dominant)

• Enteroendocrine cells – hormones (motility, appetite, digestion)

• Enterocytes – nutrient absorption; microvilli (actin‑based, static)

⭐ 5. Villi vs Microvilli vs Cilia

⭐ 6. Transport Across Epithelia

Paracellular

• Through tight junctions

• Tight claudins → very small ions only

• Leaky claudins (~1 nm) → water movement

Transcellular

• Through the cell

• Required for anything larger than TJ pores (e.g., glucose)

Water transport (always passive)

• Follows osmotic gradients

• Paracellular (if leaky)

• Transcellular via aquaporins

⭐ 7. Kidney Transport & Nephron Physiology

Water reabsorption

• Proximal tubule: ~60–70%

  • Leaky TJs + AQP1

• Descending limb: AQP1 only

• Ascending limb: No water movement (tight TJs, no AQPs)

• Distal tubule: AQP‑mediated

• Collecting duct: Vasopressin‑regulated AQP2 insertion

Glucose reabsorption

• SGLT2 (early proximal tubule): fast, reabsorbs >90%

• SGLT1 (late proximal tubule): slower, reabsorbs remainder

• GLUT2: basolateral exit

• Na⁺/K⁺ ATPase: maintains Na⁺ gradient

SGLT2 inhibitors (diabetes)

• Block SGLT2 → ~50% glucose excreted → lowers blood glucose

• SGLT1 intact → prevents hypoglycaemia + gut absorption preserved

Na⁺/K⁺/2Cl⁻ cotransporter

• Secondary active transport

• Important in ascending limb to dilute filtrate and maintain medullary osmolarity

Juxtaglomerular apparatus

• Macula densa: senses NaCl

• JG cells: release renin

• Low NaCl = low BP → renin release

⭐ 8. Intestinal Cell Turnover & Extrusion

Turnover

• Entire epithelium replaced every ~4 days

Extrusion

• Occurs at villus tip

• Driven by AJs + actomyosin contraction

• Two hypotheses: apoptotic vs live‑cell extrusion

Homeostasis

• Proliferation = elimination

• Imbalance → disease

  • Too much proliferation → polyps/cancer

  • Too much death → villus atrophy (e.g., coeliac disease)

⭐ 9. Bladder & Urothelium

• Transitional epithelium

• Extremely tight junctions (protect from toxic urine)

• Umbrella cells face lumen

• AJs crucial for stretch–relax cycles

⭐ 10. High‑Yield Exam Patterns (Based on Lecturer’s Hints)

You must be able to:

• List & describe epithelial characteristics

• Describe AJs under low vs high tension

• Explain extrusion mechanism

• Compare airway vs intestinal specialised cells

• Explain glucose absorption (SGLT1/2 + GLUT2 + Na/K pump)

• Explain water reabsorption along nephron

• Differentiate villi vs microvilli vs cilia

• Explain why stem cell mutations are dangerous

• Explain why 80–90% of cancers are epithelial