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What substances are most heavily handled/reabsorbed by the kidney?
- Na+
- Cl-
- HCO3-
- Water
- 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
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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
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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?
- K+
- the kidney has the ability to selectively secrete K+, however MOST of it is still reabsorbed
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Urea
- 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
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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
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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
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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
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Endocytosis
- 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
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Transcellular Transport
- the movement of solutes & water THROUGH epithelial cells & then into the interstitial fluid

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Paracellular Transport
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)
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Solvent Drag
- 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
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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)
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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
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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)
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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 +/H + Antiporter
• it moves Na + into tubular epithelial cells (↓ its concentration gradient) coupled to H + efflux
• Na + is then basolaterally pumped OUT of the cell into the interstitium by the Na +/K + ATPase
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Na+ reabsorption is intimately connection w/ reabsorption of what other solute?
HCO3-
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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 & CO 2 by carbonic anhydrase- by generating CO 2, 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
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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
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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

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What do inhibitors of Carbonic Anhydrase (CA) act as?
- diuretics
- 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
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What else does Na+ uptake in the proximal tubule facilitate?
• Na + 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
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Cystinuria
• 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
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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, H 2O 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
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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
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Formate/Formic Acid
• 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

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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 - reuptake
• once inside the cell, Cl - can be transported out the basolateral side via a K +/Cl - cotransporter
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Paracellular Transport Mechanism of Cl- Reuptake
• as a result of Na + & H 2O 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
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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
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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)
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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)
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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
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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)
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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)
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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)
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Na+/K+/2Cl- Cotransporter
- 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
 
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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
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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
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Does Paracellular transport occur in the Thick Ascending Limb of the Loop of Henle?
YES
• 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
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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)
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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
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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)
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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
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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
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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
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Diabetes Insipidus
- 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
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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
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What compound inhibits the apical Na+ channels of Principal Cells?
- Amiloride
- keeps Na+ in the renal tubule → water stays there → diuretic
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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
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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)
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Vacuolar ATPase (V-ATPase)
- transports protons from the epithelial cytoplasm into the tubular lumen
- is driven by ATP hydrolysis
- is critical in maintaining pH

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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
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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
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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
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Agents that ↑ NaCl &/or Water Reabsorption by the Renal Tubule
 - PT: proximal tubule
- TAL: thick ascending limb
- DT: distal tubule
- CD: collecting duct
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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
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Glomerulotubular Balance
• 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)
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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
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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
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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 (↑π c)
• 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)
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