Tubular Transport Flashcards
tight junctions
*composed mostly of zona occludens
*variable barrier to passive diffusion
*separates luminal from basolateral membrane segments
solute transport - key concepts
*transcellular reabsorption or secretion is mediated by protein carriers or ion channels to allow passage through lipid bilayer cell membrane
*basolateral Na+/K+ ATPase pump (3 Na+ out, 2 K+ in) maintains low Na+ and electronegative charge inside the cell
*Na+ enters the cell down a favorable gradient via a variety of mechanisms at different nephron sites
*tubular SECRETION happens via similar mechanisms, in reverse
solute transport - key sodium transporters
- proximal tubule:
-Na+ cotransporters with glucose, phosphate, and amino acids
-Na+/H+ antiporter - Loop of Henle:
-Na+/K+/2Cl- cotransporter - distal tubule:
-Na+/Cl- cotransporter - collecting tubule:
-epithelial Na+ channel (ENaC)
-ROMK K+ channel
glomerulus functions (overview)
*forms ultrafiltrate
proximal tubule functions (overview)
*reabsorbs majority of filtered NaCl/water
*reabsorbs majority of filtered bicarbonate
*site of ammonia production
*reabsorbs almost all filtered glucose and amino acids
*reabsorbs K, phosphate, calcium, magnesium, urea, and uric acid
*secrete organic anions (urate) and cations (protein-bound drugs)
loop of henle functions (overview)
*reabsorbs additional filtered NaCl
*counter current multiplier as NaCl is absorbed in excess of water
*magnesium excretion
distal convoluted tubule functions (overview)
*reabsorbs a small fraction of filtered NaCl
*active regulation of calcium excretion
connecting segments and cortical collecting tubule functions (overview)
*principal cells: reabsorb Na/Cl and secrete K (aldosterone)
*intercalated cells: secrete H+, reabsorb K, secrete bicarbonate in metabolic alkalosis
*reabsorb water (ADH)
medullary collecting tubule functions (overview)
*site of final modification of urine
*reabsorb Na/Cl
*reabsorb water (ADH) and urea, causing a dilute or concentrated urine to be excreted
*secrete H+ and NH3; urine pH can be lowered to 4.5-5
*reabsorption or secretion of K
early PCT (first aid)
*contains brush border
*reabsorbs all glucose & amino acids and most HCO3-, Na+, Cl-, PO43-, K+, H2O, and uric acid
*isotonic absorption
*generates and secretes NH3, which enables the kidney to excrete (via secretion) more H+
PTH and early PCT (first aid)
*PTH (parathyroid hormone) inhibits Na+/PO43- cotransport → increased excretion of PO43-
Angiotensin II & early PCT (first aid)
*Ang II stimulates Na+/H+ exchange → increased Na+, H2O, and HCO3- reabsorption (permitting contraction alkalosis)
diuretics & early PCT
*acetazolamide: blocks CA (carbonic anhydrase)
*SGLT2 inhibitors: block SGLT2
early PCT: Na+/H+ antiporter
*directly promotes bicarb reabsorption
*Ang II and NE increase activity of the exchanges (these increase in response to volume depletion)
glucose transport in PCT
*2 cotransporters:
-SGLT1: high affinity, low capacity
-SGLT2: low affinity, high capacity
*transport maximum: concentration above which tubule can no longer completely reabsorb glucose (occurs when plasma glucose ~ 300 mg/dL; results in excretion of glucose in urine)
urea transport
*reabsorption of water in proximal segments results in gradually increasing urea concentrations in the tubule, favoring passive reabsorption further down the road
Fanconi syndrome
*generalized reabsorption defect in PCT
*a clinical condition marked by urinary losses of molecules normally reclaimed by the PCT (proximal tubule):
-phosphaturia, amino aciduria, uric aciduria, glycosuria
*can be caused by a variety of diseases that damage proximal tubular cells (ex. multiple myeloma)
secretory pathways of organic cations in the PCT
*endogenous: creatinine
*exogenous: cimetidine, trimethoprim, quinidine
*enter the cell via the Organic cation transporter 1 (OCT1)
secretory pathways of organic anions in the PCT
*endogenous: urate, hippurate, ketoacids
*exogenous: PAH, penicillin, cephalosporins, salicylates, diuretics, radiocontrast media
*transported through the organic anion transporter 1 (OAT1)
ammoniagenesis in the PCT
*ammonia is produced in the proximal tubule
*key factor in acid secretion
*glutamine → alpha-keto gluturate & ammonia (NH3)
*NH3 + H+ → NH4+ (ammonium)
*NH4+ can be excreted from the cell
cortical vs. cortico-medullary nephrons
*based on the length of the loop of Henle
*outer cortical nephrons have no thin ascending limb
descending loop of Henle (first aid)
*thin, WATER PERMEABLE
*passively reabsorbs H2O via medullary hypertonicity (impermeable to Na+)
*concentrating segment
*makes urine hypertonic
ascending loop of Henle (first aid)
*thick, NaCl permeable
*reabsorbs Na+, K+, and Cl- via NKCC channel
*indirectly induces paracellular reabsorption of Mg2+ and Ca2+ through positive lumen potential generated by K+ backleak
*impermeable to H2O
*makes urine less concentrated as it ascends
Loop of Henle - general functions
*descending limb = water permeable
*ascending limb = NaCl permeable
*concentrates filtrate in loop as it goes down
*allows for efficient passive NaCl reabsorption as it ascnends
*NaCl contributes to gradient
*gradient assists with maximal urine concentration later in the collecting duct
countercurrent multiplier in the loop of henle
*allows for maximum urine concentration in the collecting duct
*water can be reabsorbed efficiently due to high gradient
*in the collecting duct: ADH required for water reabsorption even though there is a high gradient
sodium transport in the thick ascending limb of the loop of Henle
*Na+/K+/2Cl- cotransporter allows influx (reabsorption) of sodium, potassium, and chloride into the cells
*potassium leaks back out via a potassium channel
*site of loop diuretic action
calcium handling in the thick ascending limb
*potassium leaking out of the cell results in a slight electropositive charge
*this charge is used to transport calcium down the gradient para-cellularly
*high calcium detected by CaSR (calcium-sensing receptor) and inhibits the NaK2Cl channel to stop the reabsorption of calcium
Bartter’s syndrome
*mutations resulting in defective NKCC (Na+/K+/2Cl- cotransporter in loop of Henle)
*phenotype: child with hypokalemia, volume depletion (with low BP), hypercalciuria, and metabolic acidosis
presents similarly to chronic LOOP diuretic use: metabolic alkalosis + hypokalemia + hypercalciuria (loops LOSE calcium in the urine
early DCT (first aid)
*reabsorbs Na+ , Cl- (via Na+/Cl- cotransporter)
*impermeable to water
*makes urine fully dilute (hypotonic)
*site of action of thiazide diuretics
antidiuretic hormone (ADH)
*ADH is made in the hypothalamus & stored in the posterior pituitary
*released in response to blood hypovolemia & hypertonicity
*ADH binds V2 receptors and causes increase in insertion of aquaporins in the cortical collecting duct, which function exclusively as water transporters, in the luminal membrane
water reabsorption (antidiuresis) in the cortical collecting duct - ADH active
*active NaCl transport in thick ascending loop
*ADH allows for passive water diffusion down the steep gradient (aquaporins inserted)
*osmolality of urine INCREASES
water excretion (diuresis) in the cortical collecting duct - ADH absent
*active NaCl transport in thick ascending loop
*more NaCl absorption in DCT
*no ADH, so no water movement in collecting ducts
*osmolality of urine DECREASES
role of urea in the medullary gradient
*ADH helps urea concentrate in tubule
*high urea gradient promotes absorption
*if ADH has been absent, urea gradient dissipates
when the body needs to conserve water, what response occurs in the kidney?
*ADH production increases → the cortical collecting duct reabsorbs more water, producing a concentrated urine
diuretics & DCT
*thiazide diuretics: inhibit Na+/Cl+ co-transporter in DCT
calcium handling in the DCT
*major site of active calcium transport
*PTH and calcitriol increase calcium reabsorption here
*NaCl channel activity separate, but inhibition of this channel increases calcium reabsorption
*thiazide diuretics thus increase calcium reabsorption
recall: loops lose calcium, so thiazides retain calcium
Gitelman’s Syndrome
*mutations resulting in defective NaCl cotransporter in DCT (acts like a thiazide diuretic)
*phenotype: young adult with hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria
familial hyperkalemic hypertension (FHH)
*an activating mutation of NaCl channel in DCT
*sx: hypertension, hyperkalemia, metabolic acidosis, normal kidney function
*cause: inherited defect of kinases in DCT that control turning off NaCl channel; defect prevents ability to turn off, so constitutively activated
*result: increase in NaCl absorption → volume expansion, suppression of RAAS, decrease in delivery of Na+ and Cl- to collecting duct, and decrease in K+ secretion
*treatment: thiazide diuretic
principal cells in cortical collecting tubule
*primary site of K+ excretion
*electrogenic Na+ transport via ENaC (epithelial sodium channel)
*creates an electronegative gradient in the lumen, which favors K+ excretion through ROMK channels
*aldosterone binds to mineralocorticoid receptor (MR) intracellularly, where it:
-increases # of ENaC and probability of being open
-increases # of ROMK
diuretics & cortical collecting tubule
*potassium sparing diuretics
*examples: spironolactone, amiloride, triamterene
Liddle’s Syndrome
*constitutive activation of the ENaC channels (gain-of-function of ENaC) in the cortical collecting duct
*results in:
-excessive Na+ reabsorption
-excessive K+ excretion
*phenotype: HTN, low renin/aldosterone, hypokalemia, metabolic alkalosis
intercalated cells type A (alpha) in cortical collecting tubule
*main job = acid handling
*excrete H+
*can also reabsorb K+ in response to hypokalemia
intercalated cells type B (beta) in cortical collecting tubule
*shows reverse polarity of alpha type
*excrete bicarbonate
medullary collecting tubule
*main job is to fine tune NaCl, H+, and water absorption
*amiloride sensitive Na+ channel
*aldosterone sensitive
*in volume expansion: ANP causes natriuresis
*water: ADH responsive
*highly permeable to urea
renal pelvis, ureters, and bladder
*renal pelvis is modestly permeable to urea and water
*urea may move from pelvis to medulla, water opposite direction
*changes of 7-15% in urine composition can occur in ureters and bladder, depending on flow state/contact time
