Renal Chapter 4: Basic Transport Mechanisms

Question 1

Basic process of moving substances between blood and tubular lumen require solutes and water to cross what?

Answer 1

2 cell layers: tubular epithelium and vascular endothelium plus region of interstitial fluid between then

in cortex where fluxes of filtered substances are huge, vascular endothelium (peritubular capillaries) is fenestrated …fenestrae and loose underlying basement membrane offer virtually no resistance to the passive movement of water and small solutes

Question 2

What are two consequences of the fact that fenestrae and loose underlying basement membrane offer virtually no resistance to the passive movement of water and small solutes in cortex?

(Are events governed more by vascular or tubular epithelium)

Answer 2

overall transport is governed by events in tubular epithelium rather than vascular endothelium

cortical interstitium, which is the medium faced by the basolateral membranes of tubular epithelia, has an osmolality and concentration of small solutes close to those in plasma

(interstitial composition changes when plasma composition changes)

Question 3

How is transport different in medulla? (What determines properties of overall transport and what is medullary interstitium like in comparison to plasma?)

Answer 3

blood flow and transport events are lower…

only some regions of vasculature are fenestrated

so overall transport depends on properties of vascular endothelium and tubular epithelium

medullary interstitium is NOT plasma-like in its composition

Question 4

What is the paracellular route (crossing which epithelium)?

Answer 4

crossing tubular epithelium…
single step
substance goes around the cells (through matrix of tight junctions that link epithelial cell to neighbor)

Question 5

What is transcellular route?

Answer 5

crossing tubular epithelium

substance goes through the cells
2 step process: across apical membrane facing tubular lumen and across basolateral membrane facing interstitium

Question 6

Describe movement by diffusion.

Answer 6

frenzied random movement of free molecules in solution

Net diffusion occurs across barrier (more molecules moving one direction than the other) if there is a driving force (concentration gradient) and barrier is permeable

applies to all substances crossing endothelial barrier lining peritubular capillaries, and most substances taking paracellular route around tubular epithelium, some substances taking transcellular route through membranes

Question 7

What can directly diffuse across the lipid bilayer?

Answer 7

lipid soluble substances like blood gases or steroids

Question 8

What are channels?

Provide a few examples.
Describe how they open.
Is movement passive or active?

Answer 8

small pores (proteins with a “channel” or pathway through interior of a protein) that permit, depending on structure, water or specific solutes to diffuse through them

sodium channel
potassium channel
aquaporins- permeable to water

open and close so that permeability of a membrane containing lots of channels is proportional to the probability of being open

movement is passive (no external energy req.)

Question 9

What is the inherent energy driving diffusion?

Answer 9

concentration gradient or electrochemical gradient

gradients of voltage and concentration

Question 10

When might channels be gated?

Answer 10

(channels permeability is regulated by environmental factors and signaling cascades)

if gated- prob. of channel being open is increased or decreased

Question 11

Describe some types of gating channels.

How might some of these channels change expression?

Answer 11

reversible binding of small molecules that are components of signaling cascades (ligand-gated)

changes in membrane potential (voltage gated)

mechanical distortion (stretch-gated)

phosphorylation sites- P either locks shut or allows it to be gated by a mechanism above

some channels can move back and forth between surface membrane and intracellular vescicles, thereby regulating how many existing channels are actually functioning as permeability pathways

genomic expression of channels is regulated so total number is altered up or down.

Question 12

How do channels and transporters differ in regards to rate of transport?

Answer 12

channels move large amounts of materials across membranes in short period of time

transporters have much lower rate of transport bc transported solutes bind much more strongly to transport protein
(protein also much undergo a more elaborate cycle of conformational change to move the solute from one side of membrane to the other)

Question 13

Describe the mechanisms by which a transporters can be regulated.

Answer 13

changes in phosphorylation of transporter (turning its activity on/off), sequestration into vesicles, changes in genomic expression

Question 14

Describe uniporter.

What is the difference between a channel and uniporter?

Provide an example of a molecule that uses this type of transporter.

Answer 14

permit movement of single solute species through membrane

channel is a tiny hole, uniporter requires solute to bind to a site that is alternatively available to one side and then the other side of membrane

uniporter- facilitated diffusion (driven by concentration gradients but transported material moves through uniporter protein rather than membrane)

GLUCOSE -uses members of GLUT family of proteins in proximal tubule epithelial cells (move glucose from cytosol across basolateral membrane into interstitium)

Question 15

Describe symporters and antiporters.

Provide a few examples of each

Answer 15

move 2 or more solute species in the same direction (symporters or cotransport) or in opposite direction across membrane (antiporters or exchange/counter transport)

symporters- 1 or 2 Na and glucose together into cells (SGLT protein family), Na K and Cl all into cell

antiporters- (Na in, proton out (sodium hydrogen exchangers -NHE protein family)
Cl in one direction and bicarbonate in other direction

Question 16

Describe energy in diffusion, uniporter, antiport/symport

Answer 16

diffusion and uniport- energy inherent in electrocheical gradient

symport/antiport- need ENERGY (one solute moves down its concentration gradient provides the energy to move 1 or more other solute up its electrochemical gradient)

-use secondary active transport

Question 17

Describe active/secondary active transport.

Answer 17

active transport is whenever a solute moves up electrochemical gradient

but secondary active bc does not hydrolyze ATP …energy comes indirectly from transport of another solute rather than directly from chemical reaction

(Na often used by symporter or antiporter to provide energy) …energetics of sodium always favor entrance …if cell permeable to Na then it will always enter not leave the cell.

(stoichiometry. .energy available from gradient multiplied by number of molecules that move per transport cycle)
p. 62

Question 18

Describe primary active transporter. Give an example.

Answer 18

membrane proteins that are capable of moving 1 or more solutes up their electrochemical gradients using the energy obtained from hydrolysis of ATP

all transporters that use this are ATPases (structure is both that of enzyme that splits ATP and a transporter that has binding sites that alternatively are open to one side and then other side of membrane)

Na/K pump (3 Na out, 2 K in)
H-ATPases
Ca-ATPases

Question 19

Describe receptor-mediated endocytosis.

Answer 19

solute, usually protein, binds to a site on apical surface of an epithelial cell, then a patch of membrane with the solute bound to it is internalized as a vesicle in the cytoplasm

subsequent processes then degrade the protein into its constituent amino acids, which are transported across the basolateral membrane and into the blood

(apical surface to lumen, basolateral surface to basement membrane-interstitial space-blood)

Question 20

What is transcytosis? When is it important in kidney?

Answer 20

immunoglobins, endocytosis can occur at either apical or basolateral membranes, then endocytic vesicles remain intact and are transported to the opposite cellular membrane where they undergo exocytosis to release the protein intact

important in host defense and in the prevention of urinary tract infections

Question 21

How will solutes dissolved in water change concentration of water and its diffusion?

Answer 21

reduce concentration of water and therefore reduce tendency of water to diffuse out of a solution

Question 22

Describe osmosis and osmolality.

Answer 22

When solutions of a different solute concentration are separated by a barrier, water will move from more dilute solution to more concentrated solution (from where water is more concentrated to where it is less concentrated)

osmolality- ability of solutes to lower concentration of water (function of concentration and type of solute- protein better than sugar, sugar better than ion at lowering concentration of water) = osmotic pressure,
units osmoles/kg water

Question 23

Given a cell membrane or epithelial layer in which solutions on the 2 sides have different osmolalities, where will water move?

Answer 23

water will move by osmosis toward the side with higher osmolality

“water follows the osmoles”

Question 24

When is osmolality/osmotic pressure effective in driving osmosis?

Give example of when it won’t be effective in influencing movement.

Answer 24

only when barrier is less permeable to solutes than water

in fenestrated endothelial barriers of GC and peritubular capillaries, most of solutes are as permeable through the fenestrae as water and do not influence water movement …large plasma proteins are NOT permeable and therefore do influence water movement

Question 25

What does most of transport in kidney consist of?

Define iso-osmotic, what areas are iso-osmotic?

Answer 25

reabsorption (most of the 180L of water and several pounds of salt filtered each day into Bowman’s space are reabsorbed..along w other substances

much is iso-osmotic- water and solutes reabsorbed in equal proportions (filtration in glomerulus is iso-osmotic… all solutes except large plasma proteins move from plasma into filtrate in same proportion as water )
-PT- iso-osmotic mostly, later portions of nephron..NOT iso-osmotic which is important for regulation of solute and water balance

p 65

Question 26

How does tubular hydrostatic pressure affect reabsorption?

Answer 26

its several mmHg higher than interstitial hydrostatic pressure which favors reabsorption
(small influence normally)

It requires a hydrostatic
pressure gradient of 19.3 mm Hg to act as a driving force equivalent to
an osmotic gradient of 1 mOsm/kg, and the hydrostatic pressure difference is
usually not more than 5–8 mm Hg.

Question 27

What might happen if liver disease prevents normal production of serum albumin?

Answer 27

results in low plasma oncotic pressure… absorption of fluid from the cortical interstitium can be slowed, causing a backup of fluid that inhibits
fluid movement from tubular lumen to interstitium. Ultimately, this can lead to increased excretion of water and electrolytes from the body.

Question 28

What happens between capillary plasma and cortical interstitial fluid as blood flows through peritubular capillaries?

Answer 28

there is a rapid diffusion of
individual molecules back and forth between capillary plasma and cortical interstitial
fluid. The total volume of interstitial space is only 4% of the total cortical
volume, and the vascular volume is a little higher. Given the very high renal blood
flow, the solute concentrations in the interstitial fluid are essentially clamped to
those in the blood perfusing the cortex. The cortical interstitium remains quite
plasma-like (minus the proteins) in its composition, even though large amounts of
solute continuously cross through the interstitium from tubule to blood.

Question 29

Between the following pressures, which favor and which oppose uptake?

• hydraulic pressure in pertitubular capillaries of 20mmHg
• oncotic pressure in pertitubular capillaries of 33mmHg
• interstitial hydraulic pressure of 3mmHg
• interstital oncotic pressure of 6mmHg

What is net pressure for uptake?

Answer 29

Figure 4-1 (p. 66)

favoring uptake:
interstitial hydraulic pressure
oncotic pressure in peritubular capillaries

opposing uptake
hydraulic pressure in peritubular capillaries
interstitial oncotic pressure

net pressure for uptake (1-2) = 10mmHg

Question 30

What does it mean that epithelial transport requires epithelial cells to be polarized?

Answer 30

proteins present in the apical and basolateral membranes are not the same… can promote net flux of sodium from lumen to interstitium

Question 31

Draw/explain the 4 step process of salt/water transport in renal system.

Answer 31

Step 1: active extrusion of sodium via Na-K/ATPase from the cell to the interstitium
(creates low concentration of sodium within the cell so sodium moves downhill from lumen to the cell interior via ariety of symporters, antiporters and channels. This separation of charge (excess Na on interstitial side) promotes Step 2 (in step 1 any substance that enters the epithelial cells with sodium across the apical membrane must exit across the basolateral membrane)

Step 2: movement of anions through anion-specific transcellular and paracellular pathways to balance positive charge (accumulation of sodium and anions in the interstitial space produces an osmotic gradient from lumen to interstitum that promotes water movement (Step 3)

Step 4: accumulation of salt and water in interstitum promotes bult flow of solute and water into PT capillaries drive by Starling forces

Question 32

How does glucose cross apical and basolateral membranes?

Answer 32

crosses apical membrane via the Na/glucose symporter and exits BL membrane via a GLUT uniporter

Question 33

What happens in the tight junctions between lumen and interstitium as luminal concentration of solute rises (as water follows sodium and its anions across epithelium)?

What happens if 2/3 of water is removed, how much will nontransported solute change?

Answer 33

non-transported solute will increase in concentration to 3x its original value

As the luminal concentration rises, this generates a concentration gradient across the tight junctions between the lumen and the interstitium. If the tight junctions are permeable to the substance in question
(“leaky”), the substance will diffuse from the lumen to the interstitium. This is precisely what happens to many solutes (eg, urea, potassium, chloride, calcium, and magnesium) in the PT.

Question 34

How does transepithelial voltage play a role in the proximal tubule?

Answer 34

early in PT lumen is slightly negative relative to the interstitium, whereas later it is slightly positive.

This voltage enhances paracellular anion reabsorption early and reduces it later.

Question 35

Describe the re-absorption process of glucose. (Which mechanisms does it use, which does it never use?)

Answer 35

One substance that
does not get reabsorbed by the paracellular route is glucose.

First, it is transported
by the transcellular route. Second, the tight junctions are not permeable to saccharides.
Thus, it cannot diffuse no matter how large the concentration gradient might be.

Question 36

What is Tm?

What happens if it is reached?

Answer 36

upper limits to the speed with which any given solute can be re-absorbed from tubular lumen to capillary blood

if limits reached then more than usual amount of solute is not reabsorbed (left in lumen to be passed on to next nephron segment)

Question 37

Describe the types of Tm systems.

When/why is Tm reached?

Answer 37

tubular maximum-limited or gradient-limited

upper limit is reached bc transporters moving the substance become saturated; any further increase in solute concentration does not increase the rate at which substance binds to the transporter and thereafter moves through the membrane.

Question 38

Why do gradient limited systems reach an upper limit?

What is the difference between an upper rate for Tm limited system and gradient-limited system?

Answer 38

gradient limited reach upper limit bc the tight junctions are leaky and any significant lowering of luminal concentration relative to interstitium results in a leak back into the lumen as fast as the substance is transported out

(the epithelium has a significant passive permeability to the substance, usually through the tight junctions, such that the establishment of a large concentration gradient between the interstitium and lumen results
in a large passive back-leak.

upper rate for Tm limited system is a property of the transporter
upper rate of gradient-limited system is a property of the permeability of the epithelial monolayer regardless of the maximal rate of transport protein

Question 39

Explain Tm limited systems using glucose as an example.

Answer 39

Glucose is present
in plasma at a concentration of about 5 mmol/L (90 mg/dL) and is freely filtered. It is reabsorbed by the transcellular route. Glucose enters the epithelial
cells across the apical membrane via a symporter with sodium (a member of the SGLT protein family) and exits across the basolateral membrane into the interstitium via a uniporter (a GLUT protein family member). Normally, all the filtered
glucose is reabsorbed in the proximal tubule, with none remaining in the lumen
to be passed on to the loop of Henle. However, if the filtered load of glucose is abnormally high, the SGLT proteins’ upper limit for reabsorption is reached. That upper limit is the tubular maximum, or Tm, for glucose. It is the maximum rate at which the substance (glucose in this case) can be reabsorbed regardless of the luminal concentration.

Any increase in filtered load above the Tm, which for glucose represents a pathological situation, results in glucose being passed to loop of Henle

Question 40

Describe how gradient-limited systems relate to sodium.

If a epithelium was very leaky would its gradient limit be lower or higher?

Answer 40

in PT the tight junctions are quite permeable to Na. Any significant lowering of the concentration in the lumen as sodium is reabsorbed results in a large passive flux from the interstitium back into the lumen. Sodium is freely filtered and present in the luminal fluid at a concentration of about 140 mEq/L, the same as in plasma. As sodium is transported into the interstitium,
the interstitial concentration begins to rise and the luminal concentration falls.
The rise in interstitial concentration not only drives a flux of sodium into the peritubular
capillaries, but also back through the tight junctions into the lumen

Most of the sodium moves into the blood, accomplishing the goal of reabsorption, but
some does leak back into the lumen. When the concentration of sodium reaches a
sufficiently low level in the lumen, the concentration gradient between the interstitium
and the lumen drives sodium back across the tight junctions as fast as it can be transported through the transcellular pathway from lumen to interstitium.
At this point, transport through paracellular and transcellular pathways is large,
but net transport is zero: The system has established the largest gradient possible,
its gradient limit.

The leakier the epithelium, the lower is the gradient limit

In normal conditions the reabsorption of sodium is accompanied by a proportional
reabsorption of water, so that the luminal sodium concentration actually falls very little, ie, it does not reach its limiting gradient

Question 41

How would mannitol affect the reabsorption of Na and water?

Answer 41

if there is an unusually large amount of poorly reabsorbed solute in the lumen (eg, infused mannitol), this restrains reabsorption of water because nonreabsorbed osmoles remain in the lumen. In turn, less
water accompanies reabsorbed sodium. Then as sodium is reabsorbed, its luminal
sodium concentration falls and reaches the gradient limit. This reduces the amount
of sodium that is reabsorbed and leads to an osmotic diuresis

Question 42

Can substances in Tm or gradient-limited systems be reabsorbed completely?

Answer 42

solutes handled by Tm systems may, if the filtered load is below the Tm, be reabsorbed essentially completely, whereas solutes handled by gradient-limited systems are never reabsorbed completely, ie, a substantial amount always remains in the tubule to be passed on to the next nephron segment.

Question 43

Flux of a solute out of a cell, whether via a uniporter, symporter, or an ATPase, is
always a process of active transport (primary or secondary). True or false?

Answer 43

The answer is false. Flux by a uniporter is always passive, down the electrochemical

gradient. Flux by a symporter may be active depending on
direction. Flux via an ATPase is always active. (Theoretically, it could pump downhill, but this does not normally occur.)

Question 44

Reabsorption in the proximal tubule is described as being iso-osmotic, leaving the
luminal fluid isosmotic with plasma. Yet we already know from earlier chapters
that the excreted urine usually is quite different osmotically from the surrounding
interstitium. Why is the final urine not always iso-osmotic?

Answer 44

Most regions of the nephron have tight junctions that are far less leaky than those found in the proximal tubule, and most apical membranes are far less permeable to water. As a result, it is possible to sustain much
larger osmotic gradients across the epithelium in tubular regions beyond the proximal tubule. Reabsorption beyond the proximal tubule is generally not iso-osmotic.

Question 45

In the proximal tubule, the tubular epithelium is far less permeable to small solutes
than is the endothelium of the surrounding peritubular capillaries. True or false?

Answer 45

The answer is true. The tubular epithelium is quite permeable to many (but not all small solutes), but the peritubular endothelium is even more permeable.

Question 46

Low plasma oncotic pressure inhibits volume reabsorption from tubular lumen to
interstitium. Because this is plasma oncotic pressure, how can it affect transepithelial
transport?

Answer 46

Failure to move fluid from the interstitium to peritubular capillary as a result of low plasma oncotic pressure quickly leads to a backup of fluid
in the interstitial space. Since the interstitial space contains a small fraction of total volume of the kidneys, only a small increase in fluid volume
is required to generate a rise in hydrostatic pressure. Once interstitial pressure rises significantly, this drives an increasing back-leak.

Question 47

Even though values of osmolality and osmolarity differ numerically, any 2 solutions
of equal osmolarity will have equal osmolality. True or false?

Answer 47

The answer is false. Not all solutes are alike osmotically. Proteins, eg, exert far more osmotic effect mole for mole than do saccharides. In addition,
saccharides exert a somewhat higher osmotic effect than simple
salts. In this text, we sometimes simplify things by using osmolarity, when technically we should use osmolality. In most cases, this does not introduce a large error.

Question 48

Given the high volume of fluid normally moving from interstitium to blood in the
renal cortex, how can secreted substances move from blood to epithelium? Are they not going the wrong way?

Answer 48

Despite the volume flow, most solutes are close to diffusional equilibrium between plasma and interstitium. If the interstitium starts to become depleted of a substance as a result of secretion, net diffusion from
the plasma will soon replenish it.

Question 49

The Tm for glucose is set at what level?
A. Close to the normal filtered load
B. Well above the normal filtered load
C. Well below the normal filtered load

Answer 49

The answer is B. Normally, all the filtered glucose is reabsorbed, meaning that the filtered load does not saturate the transporter capacity. If either A or C was true, there would be at least some glucose in the urine.

Question 50

Define channel “gating,” and state whether changing interstitial osmolality is a
way of gating channels.

Answer 50

Gating is a process that changes the probability that a channel is open. Changes in interstitial osmolality are not known to gate channels directly. However, if a change in interstitial osmolality causes a cell to swell or shrink, the resulting change in mechanical stretch of mechanosensitive channels could gate them (this is thought to be how hypothalamic cells detect changes in plasma osmolality).