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What substances are most heavily handled/reabsorbed by the kidney?
- the kidneys filter an enormous amount of water each day: ~180 L daily
- more than 99% of that filtered volume is reabsorbed as the fluid makes its way through the renal tubule
- water, Na+, Cl-, HCO3- & 100% of filtered glucose & AAs are reabsorbed
- unless any of these substances are in excess, none should be present in the urine
On the surface such a process seems fairly wasteful - why filter so much (180 L) fluid just to then reabsorb it?
1. to remove waste products
2. to maintain solute & water homeostasis - the kidneys have to be able to balance excretion w/ intake
- by filtering this large volume & reabsorbing MOST of it, a minuscule change in the fraction of substance reabsorbed can drastically alter the excretion of that solute or water
What ion is the exception to the rule that ~100% of it will be reabsorbed as filtered fluid makes its way through the renal tubule?
- the kidney has the ability to selectively secrete K+, however MOST of it is still reabsorbed
- a breakdown product of proteins that is also an important osmolyte in the interstitial fluid of the kidney
- is important for generating a high urine osmolality
Renal Apical v. Basal
• the Apical surface of tubular epithelial cells corresponds to the INSIDE of the renal tubule, aka where the tubular fluid flows to eventually become the urine
• the Basolateral surface of tubular epithelial cells corresponds to the interstitial fluid of the medulla, where peritubular capillaries lie to pick up water & solutes reabsorbed during nephron processing
• reabsorption occurs from the tubular lumen → through the tubular epithelial cells → into the interstitium → then finally back into the blood
3 Major Types of Transporters
- 1. Passive/Facilitated Transporters: move solutes passively down their concentration gradient
- - eg. Glucose Transporter in the basolateral membrane of renal epithelial cells
- 2. Cotransporters (Symporters): move solutes in the same direction, 1 up & 1 down its concentration gradient
- - eg. Na+/Glucose cotransporter in the apical membrane; couples the downhill movement of Na+ into epithelial cells w/ the uphill movement of glucose (again) into epithelial cells
- 3. Antiporters: move solutes in opposite directions, again 1 up & 1 down its concentration gradient
- - eg. Na+/H+ antiporter in the apical membrane; couples the downhill movement of Na+ into epithelial cells w/ the uphill movement of H+ out into the proximal tubule lumen
Why is Na+ always moving downhill when being transported into a tubular epithelial cell?
- b/c of the Na+/K+ ATPase
- a transporter in the basolateral membrane of all cells in the body (not just the proximal tubule) that actively transports Na+ OUT of the cell in exchange for K+ into the cell
- the driving force for this process is ATP hydrolysis - it’s what supplies the gradient for all those previously mentioned coupled transporters
- invagination of a region of the plasma membrane to capture material in the extracellular space & internalized it within an endosome
- that material can then be trafficked to lysosomes for degradation & reutilization
- this is important in the kidney on the apical epithelial cell membrane for the uptake of PEPTIDES & PROTEINS that have somehow gotten through the filtration barrier & are now in the tubular lumen
- the movement of solutes & water THROUGH epithelial cells & then into the interstitial fluid
the movement of solutes & water BETWEEN cells through tight junctions where epithelial cells adhere to each other (again from the lumen to the interstitial space)
- when solutes are reabsorbed by moving with water taken from the renal tubule into the interstitium via a paracellular route
- happens in certain places but DOESN’T happen in others
How much of the filtered Na+, Cl-, & water are reabsorbed in the proximal tubule?
- 67% (about 2/3rds)
- such reabsorption occurs in an iso-osmotic manner b/c reabsorption of water follows uptake of solutes closely (solutes are absorbed → they create an osmotic gradient → this new gradient facilitates water reabsorption)
What is the osmolarity of the proximal tube’s tubular lumen in its beginning & at its end?
- they are the SAME
- even though all these solutes are being reabsorbed in the proximal tubule, there’s no change in osmolarity b/c water is following the ions out
- tubular osmolarity stays the same throughout the proximal tubule
What is the primary driving force for transport in the proximal tubule?
- the Na+/K+ ATPase in epithelial cells’ basolateral membrane
- it maintains a low cytoplasmic Na+ concentration (~10 mM) in the cytoplasm of tubular cells relative to the extracellular concentration which is typically ~140 mM (value for plasma)
What is the main way Na+ is reabsorbed in the 1st half of the proximal tubule?
• the most important transporter for Na+
reuptake in the 1st half of the proximal tubule is the apical Na+
• it moves Na+
into tubular epithelial cells (↓ its concentration gradient) coupled to H+
is then basolaterally pumped OUT of the cell into the interstitium by the Na+
Na+ reabsorption is intimately connection w/ reabsorption of what other solute?
Why are the proximal tubule cells secreting protons via the Na+/H+ Antiporter?
• to maintain pH homeostasis - it facilitates bicarbonate reabsorption
• effluxed protons combine w/ bicarbonate in the tubular lumen to form carbonic acid
• that carbonic acid is then converted into water & CO2
by carbonic anhydrase- by generating CO2
, a ‘gaseous form of acid’ can now diffuse into the tubular epithelial cell across the apical membrane
- • in the cell a cytoplasmic carbonic anhydrase converts it & water back into H2CO3
- • H2CO3 then dissociates into protons & bicarbonate
Proximal Tubule H+ Cycle
• recycled H+ has been used to convert luminal bicarbonate 1st into carbonic acid then CO2
• that CO2 diffuses across the apical membrane where it’s reformed into H2CO3 INSIDE the cell
• H2CO3 can then dissociate into HCO3- & H+ (which continue to promote the cycle)
• the protons here are CYCLING, there’s no net acid secretion in the proximal tubule - simply using acid as a way to reabsorb bicarbonate
How does newly formed cytoplasmic HCO3- exit the renal epithelial cell?
- it’s transported into the interstitium/back into the blood via a basolateral Cl-/ HCO3- exchanger
- (similar to BAN3 that carries out Cl-/ HCO3- exchange in RBCs)
- another mechanism is via the Na+/HCO3- cotransporter
What do inhibitors of Carbonic Anhydrase (CA) act as?
- if you block bicarbonate reabsorption, more Na+ tends to stay in the renal tubule (to maintain electroneutrality)
- the retention of solutes in the lumen KEEPS water in the tubule lumen → more fluid stays in the urine → hence it’s a diuretic
What else does Na+ uptake in the proximal tubule facilitate?
uptake is coupled to & drives the reabsorption of NUTRIENTS: glucose, sugars, AAs
- • happens via a series of Na+ couple cotransporters in the apical membrane
- - the downhill movement of Na+ into the cell is driving the uphill movement of sugars/AAs into the cell (against its concentration gradient)
• then these nutrients exit the cell via passive transporters on the basolateral side of the epithelial cell
• caused by a genetic defect in an apical Na+ coupled amino acid transporter involved in cysteine transport
• in this disease cysteine & other AAs stay in the tubular lumen & can form SALTS w/ Ca2+
• those Ca2+ salts aggregate, precipitate, & lead to the formation of kidney stones
• in this case there is a direct relationship between the absence of a Na+ coupled transporter & the appearance of kidney stones in a patient
How the Concentration of Solutes Changes as Fluid Moves Through the Proximal Tubule
• the concentration of substances like sugars, lactate, AAs, & bicarbonate are decreasing
• the concentration of Na+
remains constant b/c its uptake is happening iso-osmotically: as Na+
is being reabsorbed, H2
O follows along behind it
• b/c there isn’t much Cl-
reuptake in the 1st half of the proximal tubule, it’s concentration actually increases somewhat: this is important in the later generation of a transepithelial potential
What is the main way Na+ is reabsorbed in the 2nd half of the proximal tubule?
• here there is also an apical Na+/H+ Antiporter
• however now secreted protons aren’t combining w/ bicarbonate but instead w/ other anions like formate
• so effluxed H+ combines w/ small charged anions (formate) to form formic acid, which then diffuses back into the cell
• formate is the the unprotonated charged form
• formic acid is the protonated uncharged form
- • formic acid is actually small enough to DIFFUSE across the apical epithelial cell membrane into the proximal tubular epithelial cells
Why do cells want to reabsorb formic acid?
• once formic acid has diffused into the renal epithelial cell, it can dissociate into it’s charged form formate (HCOO−
) & a proton (H+
• this formate can then be used by an Antiporter in the apical side of epithelial cells that couples the efflux of formate back into the tubular fluid w/ the reabsorption of Cl-
• there’s a lot of Cl-
in the tubular fluid that needs to be reabsorbed & this represents a TRANScellular mechanism of Cl-
• once inside the cell, Cl-
can be transported out the basolateral side via a K+
Paracellular Transport Mechanism of Cl- Reuptake
• as a result of Na+
O being reabsorbed in the 1st part of the proximal tubule, Cl-
concentration in the tubular lumen increases
• that provides a driving force for Cl-
to move from the lumen into the interstitium paracellulary
- • this movement of a negative species creates a transepithelial potential between the lumen & interstitial space
- - this isn’t the same thing as a transmembrane potential; this gradient is much smaller
• however it still provides a significant driving force now for the uptake of additional CATIONS paracellularly
Overall Effect of Paracellular Cl- Resorption
• the uptake of Cl- ions leaves the tubular fluid more positively charged
• that transepithelial potential helps drives the uptake of Na+, K+, Ca2+, Mg2+, any cationic species can sense this potential & MOVE toward the interstitium
• *the Cl- diffusion potential (via a transepithelial gradient) is what promotes paracellular movement of cations from the tubular lumen into the interstitium
Besides the 2nd half of the proximal tubule, where else does paracellular transport occur?
1. Thick Ascending limb of the loop of Henle
2. Collecting Duct
in these 2 places the molecular bases of the transepithelial potential is less clear (unlike in the proximal tubule, where it’s clearly due to increased Cl- concentration & then subsequent movement)
How much of the filtered Na+, Cl-, & water are reabsorbed in the thin portions of the Loop of Henle?
- 25% of Na+ & Cl-
- 23% of water
- this reabsorption is happening sequentially (instead of together like in the proximal tubule)
What are the 3 distinct segments of the Loop of Henle?
• thin Descending limb: highly permeable to water but impermeable to ions
• thin Ascending limb: impermeable to water but permeable to Na+ & Cl-
• thick Ascending limb: again ion but no water reabsorption
Thin Descending Limb
• as the tubular fluid makes it’s way down the thin descending limb, it’s surrounded by an interstitium that has a HIGH osmolarity (starts at 300 mOsm, can get as high as 1200 mOsm at the bottom of the medulla)
• there’s a HUGE osmotic gradient between the lumen & the interstitium
• to equilibrate this gradient, either salt or water could move; b/c the descending thin segment is IMPERMEABLE to salt, water moves OUT of the tube into the interstitium
• therefore at the tip of the Loop of Henle, the osmolarity in the tubular lumen is equal to the interstitial osmolarity (~1200 mOsm)
Thin Ascending Limb
• impermeable to water, but permeable to salt (solutes)
- • as the fluid makes its way back up the loop of Henle, to equilibrate the osmolarity salt moves out of the tube into the interstitium
- - higher up in the medulla the interstitium has a lower & lower osmolarity (decreases from 1200 mOsm back to ~300 mOsm)
What is the special important transporter in the Thick Ascending Limb of the Loop of Henle?
- the Na+/K+/2Cl- Cotransporter in the Apical membrane (facing the tubular lumen)
- * is the most important transporter in the thick ascending limb
- it couples the downhill movement of Na+ (downhill b/c of the basolateral Na+/K+ ATPase) to the uphill movement of K+ & Cl- all into the epithelial cells
- (there’s also a Na+/H+ antiporter)
- a 1200 AA protein containing 12 transmembrane segments & 2 large cytoplasmic domains that’s driven by the (ATPase facilitated) Na+ gradient
- it allows for K+ & Cl- reabsorption
What compound inhibits the Na+/K+/2Cl- Cotransporter?
- Furosemide, a diuretic
- by blocking this transporter, more ions (solute) get left in the tubular lumen which means more water is retained there as well → more fluid ends up in the urine
In what disease is the Na+/K+/2Cl- Cotransporter defective?
- Bartter’s syndrome, which is characterized by hypokalemia
- the reason low K+ levels occur is b/c this transporter provides an important route of K+ reabsorption
Does Paracellular transport occur in the Thick Ascending Limb of the Loop of Henle?
• same as in the proximal tubule, the sign of the transepithelial potential is luminal positive relative to the interstitium; this helps DRIVE cation reuptake from the tubular lumen
• * important difference between the thin/thick ascending limb & the proximal tubule is that they’re IMPERMEABLE to water; there can be NO solvent drag here
• what IS happening at the epithelial tight junctions is like electrophoresis → ions pass through w/o being carried by water
How much of the filtered Na+, Cl-, & water are reabsorbed in the Distal Tubule & Collecting Duct?
- 7% of the filtered Na+ & Cl-
- a VARIABLE amount of water depending on the amount of ADH (Antidiuretric Hormone)
ADH (Antidiuretric Hormone)
- High ADH→ high water permeability → extensive reabsorption of water → concentrated urine
- Low ADH→ low water permeability → extensive excretion of water → dilute urine
What is the most important transporter on cells of the Early Distal Tubule?
- • Na+/Cl- Cotransporter in the apical membrane
- allows downhill movement of Na+ into the cell (driven by the Na+/K+ ATPase facilitated gradient) & secretion of Cl- into the tubular fluid
• * the early distal tubule is IMPERMEABLE to water - there is continuous salt reabsorption but no water is taken out of the tubular fluid at this point
• the fluid in the tubular lumen therefore becomes hypOosmolar (has a lower osmolarity than plasma, ~50 mOsm)
What compound inhibits the Na+/Cl- Cotransporter?
- Thiazide, a diuretic
- by blocking this transporter, more salt stays in the tubular lumen which means more water is retained there as well → more fluid ends up in the urine
What are the 2 types of cells in the Late Distal Tubule & Collecting Duct?
- 1. Principal Cells: on top
- 2. Intercalated Cells: on the bottom
What are the 3 key apical transporters in Principal Cells?
- 1. Na+ Channels
- - allow Na+ to move down its concentration gradient into epithelial cells
- 2. K+ Channels
- - critical for maintaining homeostasis: are the primary route by which the kidney can secrete K+
- 3. Water Channels, aka Aquaporins
- - are present in vesicles beneath the apical membrane & moved from these vesicles to the apical membrane in response to ADH
- occurs when a patient either fails to make or respond to ADH, meaning they’re unable to regulate water reabsorption
- they can’t increase the water permeability of the CD so a very dilute urine is being generated constitutively
The last segment of the CD reabsorbs up to how much of the filtered water?
- up to 10%
- that means if the principal cells of the late distal tubule & CD are NOT reabsorbing water, 10% of that filtered water will be lost in the urine
- b/c 180 L of fluid is filtered a day, an extra 18 L will be lost via the urine a day
- a patient w/ uncontrolled diabetes insipidus is urinating 18 L a day (10x a typical volume) - the only way they’re avoiding death by dehydration is by consuming massive amounts of water
What compound inhibits the apical Na+ channels of Principal Cells?
- keeps Na+ in the renal tubule → water stays there → diuretic
In what disease are the apical Na+ channels of Principal Cells mutated?
- Liddle’s Syndrome (*gain of function mutation)
- the mutated channels excessively reabsorb Na+, which causes ↑ BP
- is characterized by HYPERactivity of these Na+ channels
- symptom of Liddle’s syndrome = HTN, a direct consequence of excessive Na+ reabsorption in the principal cells
What are the 2 types of Intercalated Cells (other cells in the Late Distal Tubule & CD)?
- α- & β-intercalated cells
- these cells are specialized for Acid Secretion
- they have in their apical membrane an ATP-drive ion pump, the Vacuolar ATPase (V-ATPase)
Vacuolar ATPase (V-ATPase)
- transports protons from the epithelial cytoplasm into the tubular lumen
- is driven by ATP hydrolysis
- is critical in maintaining pH
A defect in one of the subunits of the Vacuolar ATPase can lead to what condition?
- Renal Tubule Acidosis
- patients are unable to secrete a sufficient amount of acid into the urine & as a result the plasma becomes overly acidic
How does the cytoplasm of Intercalated cells avoid becoming overly alkaline, what with all the acid secretion across the apical membrane?
- they secrete base (bicarbonate) across the basolateral membrane
- cytoplasmic carbonic anhydrase combines CO2 & H2O to form H2CO3, which dissociates into H+ & HCO3-
- bicarbonate is secreted across the basolateral membrane & protons are secreted across the apical membrane, maintaining the cytoplasms neutral state
What is the transepithelial potential in the late distal tubule & collecting duct?
- it is a luminal NEGATIVE potential
- as a result paracellular Cl- reabsorption occurs
Agents that ↑ NaCl &/or Water Reabsorption by the Renal Tubule
- PT: proximal tubule
- TAL: thick ascending limb
- DT: distal tubule
- CD: collecting duct
What is ADH responding primarily to?
- increased plasma osmolarity (more so than decrease BP or volume)
- as a result it only affects WATER reabsorption, not salt reabsorption
- does so by controlling aquaporins in principle cells of CD
• designed to prevent large changes in Na+ excretion when GFR changes
• when there’s uptake of water/solutes into epithelial cells from the tubular lumen & then they diffuse out into the interstitium, most of those substances are then going back into the plasma
• movement of water (& solutes) into blood is favored by Pi & πc but opposed by Pc & πi (hydrostatic/oncotic forces)
Hydrostatic Pressure (P)
- hydrostatic pressure in the interstitium (Pi) favors fluid movement into the capillary
- hydrostatic pressure in the peritubular capillary (Pc) retards fluid movement into the capillary
Oncotic Pressure (π)
- oncotic pressure in the interstitium (πi) retards fluid movement into the capillary
- oncotic pressure in the peritubular capillary lumen (πc) favors fluid movement into the capillary
What would happen if you increase GFR (glomerular filtration) at a constant RPF (renal plasma flow)?
• the concentration of proteins in the plasma leaving nephrons via the efferent arterioles will increase (b/c more of the fluid has been filtered)
• as a result of that increased protein concentration, there will be a higher oncotic pressure in the capillary lumen (↑πc
• that ensures that more reabsorbed water REENTERS the peritubular capillary (will be pulled in to dilute that ‘high’ solute concentration)
- • this phenomenon helps balance out what could be a large fluid loss as a result of increased GFR
- • (extrinsic factors can override this: ADH, ANG II, Aldosterone, NE)