Renal- Sodium and water transport

Question 1

What are the sites of sodium and water reabsorption

Answer 1

 Na
+ reabsorption relies on the presence of 𝐍𝐚
+
transporters.
 Water reabsorption relies on the presence of aquaporins.
 The distal tubule regulates water permeability.
1. Reabsorption
 In the proximal tubule, 70% of water and Na
+ are
reabsorbed.
 Filtration (glomerulus to Bowman’s capsule): 180 l/day is
filtered, and 25,000 mmol Na
+/day.
 Excretion: 1.5 l/day of water is excreted, and 150 mmol
Na
+/day.

Question 2

Describe Starling pressures in peritubular capillaries

Answer 2

 Peritubular capillaries: blood vessels that travel
alongside nephrons allowing reabsorption and
secretion between blood and the inner lumen
of the nephron. Around the loop of Henle, they
are known as the vasa recta.
 The glomerular filter retains proteins which are
greater than 70 kDa in size. Very small proteins
are filtered and are then reabsorbed in the
proximal tubule in a process of endocytosis and
are degraded into amino acids.
 Proteinuria is a pathological condition which
can damage distal segments of the tubule and
hormonal proteins such as ADH are lost in urine
and can interfere with Ca
2+ metabolism.

 Autoregulation keeps blood flow to the glomerular capillaries constant between 80-180 mmHg so filtration is constant.
 Two sets of resistance vessels (arterioles) leads to a lower hydrostatic pressure in the peritubular capillary than in other
capillaries.
 The filtration of protein-free fluid at the glomerulus leads to a higher colloid osmotic pressure in the peritubular capillary
than in the other capillaries.

Question 3

Describe the generalised renal epithelial cell

Answer 3

The apical and basolateral membrane is separated
by tight junctions between the cells.
 Apical membrane: Na
\+ rarely enters through
channels, and instead through:
o Principle cells in the collecting duct: Na
\+
passes down its electrochemical gradient
into the cell.
o 𝐍𝐚
\+ and substrate coupled transporters
in the proximal tubule.
o 𝐍𝐚
\+ exchanger in the proximal tubule.

 Basolateral membrane: 
Na
\+/K
\+ ATPase: pumps Na
\+ out of the cell.
o K
\+ channel: K
\+ flows out of the cell down its concentration gradient

Question 4

Describe the PCT and the ion exchange that goes on here

Answer 4

Glucose, amino acids and phosphates are co-transported across the luminal
membrane with Na
+.
 𝐍𝐚
+ coupled glucose transporter: there are two types:
o Coupled to 1 Na
+ ion: transports most of the glucose into the cell.
o Coupled to 2 Na
+ ions: transports the remaining glucose into the
cell, even when luminal [glucose] is very low. This speeds up the
transport of any remaining glucose.
 𝐍𝐚
+ coupled amino acid transporter: amino acids need different types of
transporters for each type of amino acid. Some are coupled with K
+ as well.
 𝐍𝐚
+ coupled phosphate transporter: important because phosphate is in
ATP, DNA etc.
 𝐍𝐚
+/𝐇
+ exchanger: only exchange in the kidney (proximal tubule segment).
 Paracellular 𝐂𝐥
− transport: Cl
− is left behind. Bicarbonate is also required, so Cl
− has to be transported, which meets a
shunt region (formed by tight junctions).
 AQP-1 (aquaporin 1): expressed in both the apical and basolateral membrane. Water can cross freely across these
aquaporins.

Question 5

How is carrier mediated transport saturable

Answer 5

Na
+ coupled glucose transporters and the other transporters
have a limited capacity. In healthy individuals, a high transport
capacity is not required as the transport capacity is hardly ever
exceeded.
 However, if plasma [glucose] (normally 5 mmol/L during
fasting) increases, glucose reabsorption reaches a maximum
rate and remains constant.
 Glucose is present in the urine if plasma [glucose] > 10 mmol/L.
At this level, the filtered concentration of glucose exceeds the
capacity of the kidneys to reabsorb glucose, so it is excreted in
the urine.
 Glucose is toxic to the kidneys.
 Amount filtered = GFR × Plasma [Glucose]

Question 6

Describe renal glycosuria

Answer 6

Defective glucose transporters with the 1 Na
+ coupled ion transporter (SGLT2).
 If there was a mutation in SGLT1 (the one that codes for the 2 Na
+ coupled ion transporter, then there would only be minor
renal glycosuria, because it would be a minimal amount of glucose left in the blood (most taken up by SGLT2).

Question 7

Describe diabetes mellitus

Answer 7

Exceeding the transport maximum in the luminal membrane causes glucose to be present in the urine.
 Excess particles in the urine causes osmotic diuresis, because the kidney excretes more water alongside these active
particles which are osmotically active.

Question 8

Describe the electrolyte exchange in the loop of henle

Answer 8

Made of the thin limbs of the loop of Henle and the thick ascending limb
of the loop of Henle (TALH).
 Thin limb: AQP-1 is expressed in the thin limbs. Cl
− channels are
expressed on both the apical and basolateral membrane, ensuring that
the water and Cl
− concentration in the tubular fluid is similar to the
concentration of the interstitium surrounding the loop of Henle.

Thick ascending limb: water impermeable and largely transport NaCl. The thick ascending limb is full of mitochondria which
is required to generate ATP for the active transport of Na
+.

Question 9

Describe the thick ascending loop of henle

Answer 9

NKCC2 is a kidney specific transporter that is a target
for an important class of saluretics. Frusemide binds to
the Cl
− binding site and inhibits the transporter.
Frusemide is specific to the thick ascending limb
because it is being concentrated in the lumen of the
kidney and is secreted into the lumen.
 Cl
− has a specific channel formed by CLC-Kb and Barttin
subunits on the basolateral membrane, which lets Cl
−
exit the cell.
 K
+ is required to that the membrane potential shifts
from the Cl
− equilibrium potential to allow the transport of Cl
−.
 Impermeable to water.

Question 10

What is the lumen positive transepithelial potential

Answer 10

K
\+ is recycled into the lumen via the K
\+ channel (ROMK) on the apical
surface.
 On the basolateral surface, although the efflux of Cl
− depolarises the cell,
the cell is polarised by the activity of the K
\+ efflux pump and the Na
\+/K
\+
ATPase.
 These lead to a lumen-positive transepithelial potential with the
paracellular shunt allowing for the paracellular transport of positively
charged ions (Na
\+, K
\+, and Ca
2+) across the epithelial layer.
 The paracellular shunt is selective for cations only, so this prevents the
back leak of Cl
−.

Question 11

Describe the distal convoluted tubule

Answer 11

Impermeable to water
 Na
+/Cl
− cotransporter is required as [NaCl] is too low to allow NKCC2 to
functions. This means more energy is required to generate the driving force
for reabsorption.
 There is a net uptake of NaCl into the cell.

Question 12

What are the cells in the cortical collecting tubule

Answer 12

1. Principle cell
    Highly regulated and is the last step of Na
   + reabsorption.
    Purely Na
   + enters on the apical surface through ENaC. ENaC is highly
   responsive to aldosterone (increases expression of ENaC) which is important
   for the regulation of fluid and Na
   + balance. If Na
   + intake is too high, ENaC is
   degraded by the ubiquitin pathway, reducing Na
   + intake.
    ROMK (K
   + channel) allows for K
   + to leave the cell via the apical surface.

2. 𝛂 intercalated cells
 Important for acid-base regulation.
 Transports H
\+ into the lumen.
 There are 2 ATPases in the luminal membrane (either purely H
\+ out or H
\+
out and K
\+ in).
 The H
\+ forms carbonic acid and carbonate. The bicarbonate is exchanged in
the basolateral membrane for Cl
−.
 Cl
− channels CLC-K and Barttin allow the efflux of Cl
− on the basolateral
membrane. 

3. 𝛃 intercalated cells
    Important for acid-base regulation.
    Secretes bicarbonate into the lumen.

Question 13

Describe the medullary collecting duct

Answer 13

Some Na
\+ reabsorption (but not much).
 No K
\+ secretion
 A few α intercalated cells.
 Water reabsorption when appropriate (regulated by vasopressin/ADH).

Question 14

Describe Bartter’s syndrome

Answer 14

Affects any of the three major ion transport systems in the thick ascending
limb of the loop of Henle.
 There are 4 flavours of Bartter’s syndrome:
o 1
st symptom: too much fluid in the womb (embryo urinating).
o 1
st flavour: ROMK. Luminal [K
+] is 1.5 times lower than [Na
+] and
[Cl
−] so recycling is important. Only some reabsorption through the
transporter occurs, leading to accumulation of fluid.
o 3
rd flavour: CIC-Kb/Barttin. Children are deaf because these are
expressed in the ear. Relatively mild, because CIC-Ka is also
expressed in the membrane, which can still transport some Cl
−.

Question 15

What is Gitelman’s syndrome

Answer 15

Affects the 𝑁𝑎/𝐶𝑙 cotransporter.
 Rarely symptomatic, as the patient can compensate by increasing
salt intake.
 Symptomatic when [𝑀𝑔
2+] is low in the plasma. Less 𝑀𝑔
2+ is
reabsorbed which is important in stabilising neuronal membrane
voltage and leads to epileptic seizures.

Question 16

What is east syndrome

Answer 16

Affects the 𝐾
\+ channel KCNJ10 in the distal convoluted tubule. This is required for the 𝐾
\+ to leak to allow the function of
the 𝑁𝑎
\+/𝐾
\+ ATPase and 𝑁𝑎
\+/𝐶𝑙
− cotransporter.
 Mutation to KCNJ16 leads to increased reabsorption of 𝑁𝑎
\+ leading to
hypertension.

Question 17

What is Liddle syndrome

Answer 17

 Gain of function of ENaC lead to hypertension.

 Loss of function of ENaC leads to pseudohypoaldosteronism.

Question 18

What are some diseases affecting water handling

Answer 18

Diabetes insipidus:
o Nephrogenic: CCD does not respond to ADH stimulation.
o Central: pituitary tumours, post-surgery.
 Nephrogenic syndrome of inappropriate antidiuresis: gain of function
in V2R (receptor for ADH)