PCT, Loop of Henle, ADH

how 70% reabsorbed, PCT microstructure, Henle medulla grad, ADH

Tubules

main site of reabsorption: filtrate → blood

urine highly concentrated (low vol)

water content varies → ADH + Aldosterone
electrolyte content varies → Aldosterone

PCT - function

65-70% filtrate reabsorption

Na+ cotransport with:

• Glucose

• Amino acids

• H+ (bicarbonate resorption)

• Phosphate

• Cl- (electrochemical gradient)

  • Travels between cells in special tight junctions → claudin proteins

• Water → aquaporins

2/3 Na+ resorbed

• Substances that remain → 3x concentration (filtrate resorbed)

PCT fluid isotonic

PCT epithelium microstructure

Brush border → apical surface microvilli

High mitochondria numbers → active transport

• Apical carrier proteins → facilitated transport

• active transport: invaginations of basolateral membrane → increase surface area for Na⁺/K⁺ ATPase pumps + other transporters that

  • help reabsorbed solutes exit the cell toward the blood

• Tight junctions between cells

(active) SECRETIONS: across the basolateral membrane (from blood in the peritubular capillaries → tubular cells → apical membrane → tubule lumen)

• organic acids and bases → secreted into filtrate

• penicillins → conc really high

Pinocytosis: proteins → vesicles → digested into amino acids

PCT faciliated transport

Apical Symporter = faciliated carrier protein

• Na+ cotransported varies

• 2Na+ with PO4²^-

  • Glucose, Amino acids, H+ } co-transported substrate

  • Glucose + Amino acids = 100% reabsorption

• Na+ & reabsorped molecule IN epithelium (high→low)

Na+/K+ pump (basolateral)

• 2K+ in, 3Na+ out → maintains high→low Na+ electrochemical gradient

• Cl- follows Na+

• transporters can be saturated → renal threshold = proportional to GFR

  • (rate of glucose excretion increases with higher GFR)

Role of PTH and FGF-23 in PCT

downregulate phosphate reabsorption in PCT

Stress induced hyperglycaemia impact PCT function

High sympathetic drive → stress

• blood glucose rises

• PCT transporters saturated

• not 100% reabsorption

• glucosuria

Bicarbonate resorption/reclamation

• PCT = reabsorption

• Ascending loop and collecting duct = generation of new HCO3-

• → important acid base balance → more basic

• HCO3- in PCT lumen

• Apical antiport: H+ in lumen, Na+ into cell → basolateral surface

• HCO3- + H+ → H2CO3

• H2CO3 → CO2 + H2O [apical carbonic anhydrase]

  • diffuses into PCT epithelium

• CO2 + H2O → H2CO3 [apical carbonic anhydrase- reversible]

• dissociation H2CO3 → HCO3- + H+

• H+ used in apical antiport with Na+ → H+ lumen, Na+ in cell

• HCO3- → diffuses across basolateral surface

  • Na+ cotransporter

  • HCO3-/Cl- exchanger

PCT proteins <69 kDa

pinocytosis (because small)

broken down by enzymes

endosome + lysosome → peptides digested

turn to blood as amino acids (faciliated with Na+)

Peritubular capillary starling forces

net colloid (oncotic) pressure

• fluid to be pulled into capillary, electrolytes travel with water

• “negative driving force” in Starling’s law

Urine volume varies

water input equation

Water input = insensible losses (sweat, perspiration..) + urinary and faecal losses

Loop of Henle

• structure and function

Countercurrent multiplier mechanism → renal medulla hypotonic solution (concentration gradient) → higher NaCl conc in medulla interstitial fluid

Longer loop → more concentrating urine

• Isotonic solution enters Loop

• Descending limb → highly water permeable (aquaporins)

• Urea recycled → controls water potential gradient

• Asc limb → ion permeable (no aquaporins)

  • Actively transports Na+, K+, Cl- out of tubule (cotransporter)

• Fluid leaving loop hypotonic - all ions actively transported out

• Concentrated medulla draws water out of desc limb

Loop of Henle

• transport mechanism

Apical surface:

• Na+/K+/Cl- cotransporter

• K+ leaks back into lumen passively

Basolateral surface:

• 2K+ in 3Na+ out (ATPase antiport)

• K+/Cl- symport into blood

  • Basolateral transporters ensure constant epithelial cell K+ concentration

  • Enables K+ passive diffusion from epithelium into lumen → most K+ recycled

5% filtered volume removed

20-30% NaCl removed into medulla and blood

Water excretion in DCT and collecting tubules

Connecting tubules + collecting duct → ADH sensitive

Water → blood via aquaporins

Urea recycled to maintain conc gradient

Urine more concentrated

ADH secretion increases when insensible/faecal (diarrhoeal) losses increase

Determinants of urine concentration ability in medulla

• Long → short loops of Henle

  • Gerbils → cats → dogs → people

• Functional nephron number

• vasa recta (blood vessels in loop of Henle) blood flow SLOW

  • prevents solutes being washed away

  • high blood flow in hyperthyroidism → inability to maintain concentration gradient

• amount of protein: protein excreted as urea adds to medullary interstital concentration gradient

  • more protein → more concentrated interstitium

Urea in the nephron

Proximal convoluted tubule (PCT)

• ~50% of filtered urea is reabsorbed (passive diffusion).

Thin descending limb of the loop of Henle

• Urea diffuses into the lumen from the medullary interstitium (which is urea-rich due to recycling from the collecting duct).

Ascending limb

• Impermeable to urea → no change in urea here.

Collecting duct (inner medullary region)

• Urea transporters (UTs) actively secrete urea into the medullary interstitium.

• High ADH levels → increase permeability to urea, allowing urea to leave the duct and enter interstitium.

  • UREA RECYCLING

ADH

Antidiuretic hormone

• Decapeptide released from posterior pituitary

• Osmoreceptors in hypothalamus (supraoptic nucleus) sense extracellular fluid osmolarity via CSF

• Increased osmolarity → increased secretion

• ADH made in supraoptic nucleus

• Travels down hypothalamo-hypophyseal tract into posterior pituitary

• Stored in secretory granules

• Released into vascular system in posterior pituitary

• Threshold for secretion → thirst

• Targets Na+ (ion most important for osmosis)

ADH (vasopressin) actions

• V1 receptors (blood vessels) → vasoconstriction

• V2 receptors (basolateral side of cortical connecting tubule + duct)

  • More easily activated

• Gs GPCRs → adenylyl cyclase → cAMP

• V2:

  • Aquaporin insertion into apical membrane → water resorbed

Diabetes insipidus

Nephrogenic diabetes insipidus

• ADH malfunction (e.g. V2 receptor or aquaporin dysfunction)

• Polyuria → polydipsia

Cushing’s → secondary = central diabetes insipidus

• cortisol supresses ADH release → polyuria → polydipsia

Water balance

minimum volume of urine needed for excretion

• water required to dissolve waste products

• amount of Na+ in ECF determines ECF volume → links to Aldosterone

Water balance dysfunction

No V2 receptors (congenital) → cannot concentrate urine → polyuria

Alcohol inhibits ADH

Corticosteroids (prednisolone) → cortisol analogue

(prevents ADH release centrally)

High cortisol levels may blunt ADH action in the kidney by:

• Downregulating V2 receptor expression (some studies suggest this happens with chronic glucocorticoid exposure).

• Altering signaling pathways downstream of V2 receptors, reducing aquaporin-2 insertion or function.

• Increasing renal blood flow and glomerular filtration, indirectly reducing medullary osmolarity gradient, making water reabsorption less effective.