Function of Renal Tubules I and II Flashcards
In which of the following nephron segments do you find the epithelium with the highest electrical resistance?
a. Proximal tubule
b. Descending limb of loop of Henle
c. Ascending thick limb of loop of Henle
d. Distal convoluted tubule
e. Cortical collecting duct
E - cortical collecting duct
The collecting duct has the highest resistance (e.g., ‘tightest’) epithelium
An 84 year old woman developed recurrent “heartburn” that she self-medicated with an over-the- counter medication (cimetidine). One week later, her serum creatinine level of 2.7 mg/dl (increased from 1.8 mg/dl). Her physician is very concerned about rapid progression of her underlying renal disease, but is also suspicious that the serum creatinine elevation may have been caused by cimetidine. Why does the physician suspect cimetidine?
a. cimetidine is a kidney toxic agent and may cause acute renal failure
b. cimetidine blocks tubular secretion of creatinine by the thick ascending limb of the loop of Henle
c. cimetidine blocks tubular secretion of creatinine by the proximal tubule
d. cimetidine is excreted in the urine and is falsely measured as creatinine by automated chemistry
e. cimetidine blocks tubular secretion of creatinine by the thick ascending limb of the loop of Henle
c. cimetidine blocks tubular secretion of creatinine by the proximal tubule
This occurs through block of organic cation transporters
Which of the following statements is NOT true about the proximal tubule?
a. 90% of filtered bicarbonate is reclaimed
b. approximately 65-70% of total filtered sodium is reabsorbed
c. glucose reabsorption is near complete under all conditions
d. organic anion secretion can be blocked by probenecid
e. the apical membrane contains numerous microvilli
c. glucose reabsorption is near complete under all conditions
This is not true in situation where plasma glucose is very high and filtered glucose
exceeds the capacity (transport maximum) of the proximal tubule
Carbonic anhydrase inhibitors will evoke which of the following changes in proximal tubular solute reabsorption?
a. Diminished Na+ reabsorption by the Na-proton exchanger
b. Elevation in Na-bicarbonate efflux from the cell on the interstitial side
c. Diminished reclaimation of bicarbonate
d. Increased generation of cytosolic carbonic acid
e. Decreased generation of tubular fluid carbonic acid
c. Diminished reclaimation of bicarbonate
This is the main effect of carbonic anhydrase inhibitors
How thick are the cells which line the tubular segments?
monolayers with tight junctions
The apical segment of the tubular endothelium faces: lumen or interstitium
lumen
the basolateral segment of the tubular endothelial cell faces the: lumen or interstitium?
interstitium
Tight junctions are composed of what two protein types?
zona occludens and zonula adherens
The movement of fluid and solutes sequentially across the apical and basolateral cell membranes (or vice versa) mediated by transporters, channels and pumps is called…
cellular transport
movement of fluid and solutes through the narrow passageway between cells is called …
paracellular transport
When and how does paracellular occur?
when tight junctions are “Leaky”
Leaky epithelium has: low or high resistance
low
tight epithelium has: low or high resistance
high
The proximal tubule is an example of a : low or high resistance segment
low resistance due to leakiness
The collecting duct is representative of: low or high resistance
high resistance due to tight junctions
Which of the following are reabsorbed by up to 60% in the proximal tubule?
water sodium glucose/aa bicarbonate peptides
water and sodium
Which of the following are reabsorbed by up to 100% in the proximal tubule?
water sodium glucose/aa bicarbonate peptides
glucose/aa
Which of the following are reclaimed by up to 90% in the proximal tubule?
water sodium glucose/aa bicarbonate peptides
bicarbonate
Which of the following are endocytosed and degraded in the proximal tubule?
water sodium glucose/aa bicarbonate peptides
peptides (i.e. insulin etc)
Reabsorption of what ion in the proximal tubule is the driving force for solute transport?
sodium
Is the proximal tubule an example of iso osmotic reabsorption? what does this mean?
yes, the fluid leaving the tubule has an osmolality similar to plasma
How is H+ trapped in the lumen of the proximal tubule?
via metabolism of glutamine into ammonia
HOw many parts does the PT epithelium have?
3 - s1, S2, S3
What is the S1 segment of the PT epithelium?
The S1 segment is highly convoluted and is the earliest part of the PT.
What is the S2 segment of the PT epithelium?
A more distal portion of the convoluted part of the PT is called the S2 segment
What is the S3 segment of the PT epithelium?
the last part of the PT before its junction with the descending limb of the loop of Henle is called the S3 segment (a.k.a. proximal straight tubule or pars recta).
What part of the nephron is composed of microvilli/brush border on the apical side?
the PT - increases surface area for reabsorption
What transport mechanisms does the PT use?
endocytosis, cellular and paracellular
What drives paracellular movement of water and solutes in the PT?
occurs by diffusion and convection driven by the high oncotic pressure and low hydrostatic pressure within the peritubular capillaries.
How does sodium removal from the cell by the ATPase favor water reabsorption?
The removal of Na+ and other solutes from the tubular fluid creates small local osmotic gradients favoring water reabsorption through both the cellular pathway (through water channels) and the paracellular route.
Define glomerulotubular balance
Physiological adjustments in GFR mediated by changing efferent arteriolar tone cause proportional changes in tubular fluid reabsorption
For example, vasoconstriction of the efferent arteriole by angiotensin II will increase glomerular capillary hydrostatic pressure but lower pressure in the peritubular capillaries. At the same time, increased GFR and increased filtration fraction cause a rise in oncotic pressure near the end of the glomerular capillary. What is this an example of?
glomerulotubular balance
What effect does lowering hydrostatic pressure and increasing oncotic pressure by efferent arteriole vasoconstriction have on the driving force for liquid absorption in the peritubular capillaries?
increases it
What drives H+, aa, phosphate and glucose transport in the PT?
sodium coupling
What direction does the Na/H transporter move solutes in the PT?
H moves into lumen, Na into cell
What direction do Na/solute cotransporters OTHER than the Na/H antiporter move solute in the PT?
both Na and solute move into the cell
Other than the Na/K ATPase, how can sodium enter the interstitium in the PT?
Bicarb/Na symporter and paracellularly
How is Cl reabsorbed in the PT?
cellular (Cl/formate exchange) and paracellular
How is Cl cellular transport achieved in the PT?
from lumen to cell: Cl/formate exchanger
cell to interstitium: Cl/K symporter
How are formate ions exchanged for Cl in the PT?
Formate/formic acid recycling:
formate ions inside the cell form by equilibration of formic acid, then excreted into the lumen in exchange for Cl. In the lumen, formate ion equilibrates to formic acid, which can diffuse through the membrane down it’s concentration gradient
Which form of formic acid can diffuse freely from lumen to cell: formic acid or formate ion?
formic acid
How does water reabsorption occur in the PT?
cellular (AQP 1) and paracellular
Where are aquaporins located in the PT?
apically and basolaterally
What provides the driving force for water reabsorption in the PT?
osmotic gradients created by sodium reabsorption move water into the higher osmolality intercellular space
What drives the paracellular reabsorption of water in the PT?
oncotic pressure is high in the peritubular capillaries
What enzyme is important for the bicarbonate reclamation of the PT?
carbonic anhydrase in the microvilli and cytoplasm
Where is bicarb titrated in the nephron? what transporter is important for this?
lumen, forms carbonic acid by addition of proton (provided by Na/H antiporter)
Where does carbonic acid dissociate into water and CO2 in the PT?
in the microvilli, by action of CA
In what form can bicarbonate diffuse passively across the membrane in the PT?
as water and CO2
Once diffused into the cell as water and CO2, what happens to bicarb?
it is turned into carbonic acid by CA again, then immediately dissociates into bicarbonate
How does bicarb exit the PT cell on the basolateral side?
via the Na/bicarb co transporter
What is the stoichiometry for movement of Bicarb and sodium on the basolateral side of the PT cell?
3 to 1 bicarb to sodium
If filtration of bicarb exceeds the renal bicarbonate threshold, what happens in the PT?
bicarb will be secreted because the bicarb/Na co transporter will be saturated
What effect do CA inhibitors have on bicarb reclamation?
they block it, leading to metabolic acidosis
In the PT, what is true of glucose plasma and tubular fluid concentrations?
they are equal because glucose is freely filtered
What mediates glucose uptake in the PT cells?
Na/glucose co transporters (SGLT2)
What mediates glucose transport into the interstitium at the PT?
GLUT transporter
What happens when glucose is filtered in excess of the renal threshold?
Na/Glucose transporters are saturated and glucose is excreted
What effect does glucose trapping in the lumen due to hyperglycemia have on water reabsorption?
decreases drive for water reabsorption, so urine is more diluted (osmotic diuresis)
Which organic anions are transported into the PT? why?
Organic anions transported by these systems include urate, dicarboxylic acid anionis, ketoacid anions and several drugs that are highly protein-bound and not filtered at the glomerulus (penicillins, cephalosporins, salicylates)
Probenecid inhibits renal organic (anion or cation) secretion
anion
What organic cations are transported into the PT? why?
Organic cations transported by these systems include choline, dopamine, acetylcholine and creatinine. not filtered at the glomerulus
What role does p glycoprotein have in PT secretion?
secretion of certain drugs occurs exclusively via Pgp
What effect would blocking p glycoprotein have on PT secretion?
it would stop secretion, leading to higher serum concentrations
What pathways is competed for between cimetidine, trimethoprim, and creatinine?
organic cation transport
How are amino acids reabsorbed in the PT?
via sodium dependent and independent transporters that are specific for certain groups of amino acids
Mutations in either SLC3A1 or SLC7A9 at the level of the PT impair reabsorption of which amino acids and
causes which disease?
cysteine, leads to cystinuria (excess urinary cystine leading to kidney stones)
vacuolar H-ATPases and chloride channels are important for what process?
acidification of endosomes that degrade small peptides in the PT
Dent’s disease and kidney stones are caused by what altered process?
Impaired acidification of endocytic vesicles because of mutations in a PT Cl– channel gene (CLCN5) cause low molecular weight proteinuria (Dent’s disease) and kidney
stones (etiology unclear)
Where is Vitamin D activated in the nephron?
the PT
Activation of vitamin D occurs in PT through enzymatic 1-α-hydroxylation of 25-hydroxy vitamin D produced by the liver. 1,25-dihydroxy vitamin D (calcitriol) is the most potent
metabolite
What buffers improve renal excretion of H in the PT?
ammonium
HOw is ammonia generated in the PT?
Ammonia (NH3) is generated by the proximal tubule through the enzymatic breakdown of glutamine to glutamate by glutaminase.
Can ammonia or ammonium diffuse across the cell into the lumen?
ammonia
Which of the following statements about the Loop of Henle is FALSE?
a) The Loop of Henle contains the transporter targeted by loop diuretics.
b) The luminal fluid at the end of the Loop of Henle is hypotonic.
c) The descending limb is water impermeable.
d) Bartter’s syndrome is an inherited disorder of the thick ascending limb.
a) The Loop of Henle contains the transporter targeted by loop diuretics.
True! It’s the Na/K/2Cl co-transporter
b) The luminal fluid at the end of the Loop of Henle is hypotonic.
True! This is a nephron segment responsible for diluting tubular fluid. This is
accomplished by reabsorbing NaCl without water. c) The descending limb is water impermeable.
False! The descending limb is highly water permeable – a key feature that underlies the counter current multiplier effect.
d) Bartter syndrome is an inherited disorder of the thick ascending limb.
True! Bartter syndrome can arise from mutations in several genes encoding either the Na/K/2Cl co-transporter, apical K channel, and basolateral Cl channel.
In which of the following nephron segments do you find the electroneutral, thiazide-sensitive, sodium- chloride co-transporter?
a) Proximal tubule
b) Descending limb of loop of Henle
c) Ascending thick limb of loop of Henle
d) Distal convoluted tubule
e) Cortical collecting duct
distal convoluted tubule
In which of the following nephron segments will aldosterone regulate sodium reabsorption?
a) Proximal tubule
b) Descending limb of loop of Henle
c) Ascending thick limb of loop of Henle
d) Distal convoluted tubule
e) Cortical collecting duct
cortical collecting duct
In Liddle syndrome, activating mutations of the epithelial sodium channel located in the apical membrane of cortical collecting duct principal cells leads to aldosterone-independent sodium reabsorption, volume expansion and hypertension. Which of the following treatment strategies should be most effective in this disorder?
a) Furosemide (a loop diuretic)
b) Amiloride (a potassium-sparing diuretic)
c) Acetazolamide (a carbonic anhydrase inhibitor)
d) Cortisone (a glucocorticoid)
amiloride (K sparing diuretic) - blocks ENac and reverses defect
Which of the following statements about calcium absorption in the distal convoluted tubule is true?
a) Calcium reabsorption is inversely related to sodium absorption.
b) Calcium reabsorption is blocked by thiazide diuretics.
c) Calcium reabsorption is largely a paracellular process.
d) Calcium reabsorption is inhibited by parathyroid hormone.
a) calcium reabsorption is inversely related to sodium reabsorption
True! When Na is reabsorbed by the distal convoluted tubule, the elevated intracellular Na concentration blunts the driving force on Na/Ca exchange; this in turn blunts the driving force for Ca entry through an apical membrane Ca channel (because intracellular Ca levels are higher).
Which limb of the loop of Henle is water permeable?
descending limb
Where is magnesium and calcium reabsorbed (primarily) via a paracellular process?
loop of henle
compared to plasma, is fluid leaving the loop of henle hypertonic or hypotonic?
hypotonic
What are the 3 segments of the loop of Henle?
descending thin, ascending thin, ascending thick
where is the macula densa located?
thick ascending limb
How does most solute reabsorption occur in the loop of Henle?
cellular transport
what co transporter is responsible for solute transport in the thick ascending limb?
Na/K/2cl co transporter
what provides the driving force for the Na/K/2Cl co transporter in the TAL?
sodium
What is the rate limiting solute for the Na/K/2Cl co transporter in the TAL ?
potassium
How is potassium rate limiting of the Na/K/2Cl cotransporter overcome in the TAL ?
this is overcome by K+ recycling through an apical potassium channel. This K+ recycling contributes to a slight positive electrostatic charge in the lumen (relative to the interstitium) promoting divalent cation (Mg2+ and Ca2+) reabsorption through the paracellular pathway.
What ion is responsible for promoting paracellular Mg and Ca reabsorption in the TAL?
potassium creates a positive electrostatic charge in the lumen relative to the interstitium
How do chloride ions leave the basolateral side of the TAL?
via a chloride channel
What do loop diuretics target specifically?
the Na/K/2Cl cotransporter in the TAL
Barterr’s syndrome is an inherited disorder of what part of the nephron?
TAL
What are the effects of Barterr’s syndrome, which impairs the function of the NA/K/2Cl co transporter, ROMK, and or the basolateral chloride channel in the TAL?
salt wasting, hypokalemia and metabolic alkalosis
What is the name for the apical potassium channel in the TAL? Which direction does it move solute?
ROMK - recycles potassium into the lumen
What regulates NaCl reabsorption in the TAL?
a calcium sensing GPCR receptor (CaSR) which uses cAMP and eicosanoids
what syndrome is caused by loss of function mutations in the CaSR of the TAL?
familial hypercalcemic hypocalcuria - poor response in TAL to extracellular calcium
What do mutations in the paracellin-1 protein of the tight junction of the TAL cause?
familial hypomagnesemia with hypercalcuria and nephrocalcinosis
- Implies TAL has a magnesium selective ion conductance
What role does the loop of Henle have in urine concentration?
The role of the loop of Henle in water balance and urinary concentrating ability is to establish a hypertonic interstitial environment in the renal medulla.
What forms the hypertonic medullary interstitium around the loop of Henle?
the counter current multiplication caused by the opposite flow of the loop of Henle and the vasa recta
What effect does reabsorption of NaCl in the TAL have on the tubular fluid?
causes dilution of the fluid and adds new osmoles to the medullary interstitial fluid
Where is urea recycled from in the medullary interstitium?
the collecting duct
The TAL and the collecting tubule (corticomedullary portions) are: permeable or impermeable to urea?
impermeable
Under what conditions is urea concentrated in the tubular fluid of the collecting tubule?
when ADH makes the collecting duct permeable to water
When does the collecting duct become permeable to urea?
the inner medulla
Where does the vasa recta come from?
specialized peritubular capillaries that come from the efferent arteriole of the juxtomedullary nephron
The endothelial cells of the vasa recta are: permeable or impermeable to water and solutes?
permeable
Why is the osmolality of the plasma in the descending side of the vasa recta lower than the interstitum and higher in the ascending side?
Flow in the capillary is too fast to allow for complete equilibration between the plasma and the interstitium as the capillary travels along the descending and ascending limbs of the loop of Henle. As a result, the osmolality of the plasma on the descending side is slightly lower than the interstitium, while on the ascending side it is slightly higher than the interstitium. Therefore, plasma at the distal end of the capillary (alongside the ascending limb) is slightly hyperosmotic.
At the distal end of the vasa recta, what is true of the plasma?
it is hyperosmotic compared to the ascending limb of the loop of henle
How is solute trapped in the medulla?
recycling of solutes in the vasa recta
Where does transcellular mg and ca reabsorption occur?
DCT
Where in the nephron is there no paracellular transport?
the DCT
What is the main NaCL transporting pathway in the DCT?
the Na/Cl co transporter
What is targeted by thiazide diuretics?
Na/Cl co transporter in the DCT
Other than the TAL, what is an important site of calcium reabsorption?
The DCT is also an important nephron segment for the reabsorption of Ca2+ which is mediated by passive apical entry through a Ca2+ selective channel (TRPV5) and basolateral extrusion by an electrogenic Na+/Ca2+ exchanger
Is calcium reabsorption proportional or inverse to sodium reabsorption in the DCT?
inversely proportional
What effect does blocking the apical Na/Cl tco transporter in the DCT have on calcium reabsorption?
Blocking apical Na+/Cl– co-transport with a thiazide diuretic will reduce intracellular Na+ and favor basolateral Na+/Ca2+ exchange. This will improve the inward gradient for passive apical Ca2+ entry.
Which hormone stimulates calcium reabsorption in the DCT?>
parathyroid
Gitelman syndrome, which is a salt wasting disorder associated with hypokalemia, metabolic alkalosis and hypocalcuria, is caused by which loss of function mutation?
Loss-of-function mutations of SLC12A3 encoding the apical Na+/Cl– co- transporter cause Gitelman syndrome.
what is potassium secretion dependent on in the CCD?
sodium reabsorption and mineralocorticoids
Which cells in the CCD are involved in acid base control?
the intercalated cells
what are the two cell types found in the CCD?
principal and intercalated cells
Which cell types in the CCD are targeted by aldosterone, potassium sparing diuretics, and spironolactone?
principal cells, which regulate sodium reabsorption
Type A intercalated cells in the CCD regulate: acid or base secretion?
acid secretion and bicarb reabsorption
Type B intercalated cells in the CCD regulate: acid or base secretion?
bicarb secretion and acid reabsorption
What channel is responsible for sodium reabsorption in the CCD?
ENaC
What hormone regulates ENaC in the CCD?
aldosterone
What hormone regulates potassium secretion in the CCD?
aldosterone
What effect does aldosterone have on the NEDD4-2 protein involved in ENaC recycling?
leads to its phosphorylation, impairing it and keeping ENac channels on the membrane to absorb more sodium
What effect does chronic stimulation of principal cells by aldosterone have on the basolateral membrane of the CCD?
causes the basolateral membranes become highly infolded (increased surface area) and have greatly increased Na-K ATPase activity.
How do amiloride and triamterene work?
Amiloride and triamterene block ENaC directly causing reduced Na+ reabsorption.
How does spironolactone work?
Spironolactone is an aldosterone receptor antagonist and works by reducing aldosterone-stimulated Na+ reabsorption
What 2 forces regulate potassium secretion in the CCD?
First, the high intracellular K+ concentration (generated by the Na-K ATPase) creates a favorable concentration gradient for K+ secretion into tubular fluid. Secondly, during the reabsorption of Na+ without an accompanying anion, the tubular lumen becomes negative relative to the cell interior creating a favorable electrical gradient for secretion of cations. When Na+ reabsorption is blocked, the electrical driving force for K+ secretion is blunted.
In addition to intracellular potassium concentrations and reabsorption of sodium without anions in the CCD, what contributes to potassium secretion?
fast tubular fluid flow rates
What kind of transport do intercalated cells use in the CCD?
active H+ transport by a H+-ATPase (“proton pump”) and anion
exchange by a Cl–/HCO3– exchanger.
In addition to the microvilli and cytoplasm of the PT, where else in the nephron is carbonic anhydrase important?
the cytoplasm of intercalated cells in the CCD
What protein mediates whether or not Type A or Type B cells are principally active in the CCD?
hensin
In a type A cell, is the potassium - H exchanger and proton pump on the apical or basolateral side?
apical
In the type B cell, is the bicarb/cl antiporter on the apical or basolateral side?
apical
Where on the nephron does natriuretic peptide work?
the inner medullary collecting duct
What is the unique morphological trait of the IMCD epithelium?
Cells of the IMCD form a very tight, high resistance epithelium which morphologically is distinct by the presence of a single long cilium on the apical membrane (it’s speculated that this monitors fluid flow rates)
How does ADH stimulate water reuptake?
Vasopressin (a.k.a. antidiuretic hormone or ADH) binds to the V2 receptor on the basolateral membrane and triggers an intracellular signaling cascade through G-protein mediated activation of adenylyl cyclase resulting in an increase in cyclic AMP (cAMP) levels.
What effect does ANP and urodilatin have on the ability of IMCD cells to absorb sodium?
inhibits them
How does ANP cause inhibition of sodium reabsorption by the IMCD?
Secretion is triggered by volume expansion (stretching of atrial wall). Urodilatin is made by the renal tubule (probably distal to loop of Henle). Natriuretic peptides interact with either apical (urodilatin) or basolateral (atrial natriuretic peptides) receptors on inner medullary collecting duct cells to stimulate guanylyl cyclase and increase levels of cytoplasmic cGMP.
is potassium absorbed or secreted in the IMCD?
secreted
