Tubular Transport Flashcards by Kyra Porter

tight junctions

*composed mostly of zona occludens
*variable barrier to passive diffusion
*separates luminal from basolateral membrane segments

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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

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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

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glomerulus functions (overview)

*forms ultrafiltrate

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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)

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loop of henle functions (overview)

*reabsorbs additional filtered NaCl
*counter current multiplier as NaCl is absorbed in excess of water
*magnesium excretion

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distal convoluted tubule functions (overview)

*reabsorbs a small fraction of filtered NaCl
*active regulation of calcium excretion

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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)

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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

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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+

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PTH and early PCT (first aid)

*PTH (parathyroid hormone) inhibits Na+/PO43- cotransport → increased excretion of PO43-

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Angiotensin II & early PCT (first aid)

*Ang II stimulates Na+/H+ exchange → increased Na+, H2O, and HCO3- reabsorption (permitting contraction alkalosis)

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diuretics & early PCT

*acetazolamide: blocks CA (carbonic anhydrase)
*SGLT2 inhibitors: block SGLT2

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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)

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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)

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urea transport

*reabsorption of water in proximal segments results in gradually increasing urea concentrations in the tubule, favoring passive reabsorption further down the road

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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)

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secretory pathways of organic cations in the PCT

*endogenous: creatinine
*exogenous: cimetidine, trimethoprim, quinidine
*enter the cell via the Organic cation transporter 1 (OCT1)

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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 ## Footnote 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** ## Footnote 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