Lecture 19 Flashcards
What is the risk associated with high Na+ in the diet?
This can lead to high blood pressure which can lead to cardiovascular disease
What is normal blood pressure?
What is high blood pressure?
What is low pressure?
120/80 mmHg
180/110 mmHg
90/50 mmHg
What is the daily source of Na+? How much is this?
This comes from dietary intake
100 to 300 mmol/day
What are the daily losses of Na+?
How much are each of these?
sweat: 20 to 50 mmol/day
shit: 5 to 10 mmol/day
urine: few to 500mmol/day
vomit, diarrhoea, menstruation
What is the normal ECF and ICF concentrations of Na+?
ECF: 150 mM
ICF: 10 mM
Daily Na+ gain equals what? What does this means in terms of the net loss and gain?
What maintains this homeostasis?
Daily Na+ gain = daily Na+ loss
net loss and gain = 0
the nephrons maintain this
What is the daily filtered load of Na+?
filtered load = GFR x [Na+]plasma
180 L/day x 150mmol/L
27,000 mmol Na+/day
Which parts of the nephron are permeable to Na+?
- Proximal tubule (both the convolutes and straight)
- thin and thick ascending loop of Henle
- distal tubule (early and late)
- collecting duct
Which parts of the nephrons are impermeable to Na+?
the thin descending loop of Henle
Which of the following statements is TRUE?
A. The extracelular fluid Na+ concentration is 170
mM.
B. Normal blood pressure is 150/90 mm of Hg.
C. If you have a high NaCl diet you will excrete more
Na+ than normal.
D. All segments of the Nephron can reabsorb Na+.
C. If you have a high NaCl diet you will excrete more
Na+ than normal.
How do the nephrons handle the filtered load of Na+?
they due this through transporters in the apical and basolateral membrane
How much of the 27,000 mmol of Na+ than enter the proximal tubule is reabsorbed here?
18,000 mmol
After some Na+ is reabsorbed in the proximal tubule, how much enters the thin and thick ascending loop of Henle?
9000 mmol
How much of the 9000 mmol of Na+ that enters the thin and thick ascending loop of Henle is reabsorbed?
7000 mmol
After some Na+ is reabsorbed in the proximal tubule and thin and thick ascending loop of Henle, how much enters the distal tubule?
2000 mmol
How much of the 2000 mmol of Na+ that enters the distal tubule is reabsorbed here (total early and late)?
1200 mmol
After some Na+ is reabsorbed in the proximal tubule, thin and thick ascending loop of Henle and the distal tubule, how much enters the convoluted tubule?
800 mmol
How much of the 800 mmol of Na+ that enters the convoluted tubule is reabsorbed here? How much is excreted (not reabsorbed)?
600 mmol reabsorbed
200 mmol reabsorbed
What percentage of the filtered load of Na+ is reabsorbed in the proximal tubule?
67%
What percentage of the filtered load of Na+ is reabsorbed in the thin and thick ascending loop of Henle?
25%
What percentage of the filtered load of Na+ is reabsorbed in the distal tubule?
5%
What percentage of the filtered load of Na+ is reabsorbed in the convoluted tubule?
3%
What percentage of the filtered load is excreted?
1%
Which part of the nephron is known as the powerhouse?
proximal tubule
What sort of epithelium do the proximal tubule have? What does this mean in terms of the resistance and methods of transport?
- leaky absorptive epithelium
this means that they have low resistance and paracellular and transcellular transport
What are three examples of Na+ coupled apical transporters in the leaky absorptive epithelium in the proximal tubules? These are all examples of what type of transport?
- Na+/glucose cotransport
- Na+/H+ exchangers
- Na+/amino acid cotransporters
these are all examples of secondary active transport
Describe how the Na+/glucose transporter works in the proximal convoluted tubule
SGLT2 sits in the apical membrane and uses the downhill gradient of Na+ into the cell to also bring glucose into the cell. Glucose crosses the basolateral membrane via the GLUT2 transporter. Na+ is exchanged for K+ at the basolateral membrane by Na+/K+ ATPase. K+ is now in the cell but it leaves the basolateral membrane via a K+ channel
How many subunits do both SGLT1 and SGLT2 have?
4
Describe SGLT2
- where is it?
- what does it do?
- affinity and capacity?
- ratio of Na+ to glucose? What does this mean?
- inhibited by what?
- in the proximal convoluted tubule
- bulk of the glucose reabsorption (90%)
- low affinity for glucose, high capacity
- 1:1 Na+ to glucose stoichiometry so electrogenic
- inhibited by phloridzin
What is the difference between affinity and capacity?
affinity refers to how easily glucose binds to the receptor and capacity refers to the transport rates
Describe SGLT1
- where is it?
- what does it do?
- affinity and capacity?
- ratio of Na+ to glucose? What does this mean?
- inhibited by what?
- in the proximal straight tubule
- fine tuning of the glucose reabsorption (10%)
- high affinity for glucose in low conc, low capacity
- 2:1 Na+ to glucose stoichiometry so electrogenic
- inhibited by phloridzin
Describe how the Na+/H+ exchanger works in the proximal tubule
NHE (such as NHE3) is in the apical membrane and exchanges one Na+ (into the cell) for one H+ (out of the cell)
The H+ comes from carbonic anhydrase converting CO2 and H2O into H+ and HCO3-.
HCO3- and Na+ leave together through the basolateral membrane via the NBC1 channel.
There is a Na+/K+ ATPase on the basolateral membrane which allows Na+ out and K+ in and then K+ exits the basolateral membrane via a leak channel
Which isoform of the Na+/H+ exchanger NHE is the dominant apical membrane isoform?
NHE3
What are the isoforms of NHE that are in the kindey?
NHE1, NHE2, NHE4
What is the purpose of NHE3?
It moves Na+ down its concentration gradient for exchange of H+ up its concentration gradient. It is used in pH balance
Which of the following statements is FALSE?
A. The Proximal tubule is the ‘powerhouse’ of the Nephron.
B. 100% of filtered glucose is reabsorbed by the SGLT2 and SGLT1 of the Proximal tubule cells.
C. If you have a high NaCl diet you will excrete more Na+ than a person who has a NaCl normal.
D. SGLT2 has a higher affinity for glucose than SGLT1
D. SGLT2 has a higher affinity for glucose than SGLT1
What is the cotransporter in the thin and thick ascending loops of Henle?
Na+/K+/2Cl- cotransporter (NKCC2)
Describe the absorption of Na+ in the thick ascending loop of Henle
NKCC2 brings in 2Cl- ions, an Na+ ion and a K+ ion into the cell. K+ leaves the apical membrane via the ROMK channel. Na+ is brought into the cell in exchange for H+ via the NHE3 at the apical membrane. The H+ comes from carbonic anhydrase converting CO2 and H2O into H+ and HCO3-.
Na+ is pumped out of the cell in exchange for K+ be Na+/K+ ATPase in the basolateral membrane. Cl- leaves the cell through Cl- leak channel on the basolateral membrane. It also leaves cotransported with K+ at the basolateral membrane. HCO3- is pumped out of the cell in exchange for Cl- coming into the cell by AE2 at the basolateral membrane
How many different types of Barter syndrome are there?
3
What causes the three different types of Barter syndrome?
- when the NKCC is malfunctioning which leads to the loss of Na+
- mutation of the ROMK K+ channel
- mutation of the Cl- channel in the basolateral membrane
NKCC2 does what to Na+, Cl- and K+?
It moves Na+ and Cl- move down its concentration gradient and K+ against its concentration gradient
What is NKCC2 selectively inhibited by?
it is selectively inhibited by “loop diuretics” bumetanide and frusemide
How many mmol of Na+ is received by the distal tubules each day?
2150 mmol
The early distal tubule has transport function similar to the what?
thick ascending loop of the loop of Henle
The late distal tubule has transport function similar to what?
the collecting duct
How many mmol of Na+ do the distal tubules reabsorb? What percent of the daily filtered Na+ load is this?
1350 mmol
5%
Which transporters are in the distal tubule?
- Na+/Cl- cotransporter (NCCT) is in the early distal tubule
- Na+ channels (ENaC) is in the late distal tubule (and collecting duct)
Describe the absorption of Na+ in the early distal tubule
Na+ and Cl- are cotransported across the apical membrane into the cell via NKCC. K+ and Cl- are cotransported out of the cell via the lateral membrane. Cl- and K+ also flow out of the basolateral membrane via their respective leak channels. Na+/K+ ATPase is also working in the basolateral membrane
NCC have what percentage similarity to NKCC1?
60%
What is NCC inhibited by?
thiazide diuretics
Which of the following statements is TRUE?
A. Cells of the Thin and Thick Ascending Loops of Henle
reabsorb 30% of the filtered Na+.
B. The Na+-Cl- cotransporter is the main transport protein that secretes NaCl by the Thin/Thick Ascending Limbs.
C. The Na+-K+-2Cl- cotransporter is inhibited by thiazide diuretics.
D. The cells of the Distal Tubule reabsorb 5% of the filtered Na+
D. The cells of the Distal Tubule reabsorb 5% of the filtered Na+
What type of epithelium does the collecting duct have? What does this mean for the resistance and movement?
tight absorptive
this means that there is high resistance and transcellular movement
What channel does the collecting duct have?
What is this blocked by?
apical ENaC channel blocked by amiloride
How many subunits does ENaC have? What are these called?
3
and α, β, γ
How many transmembrane domains does each subunit of ENaC have?
2
What does each subunit of ENaC have?
a large extracellular loop
What motif does ENaC have? Where is it? What does this consist of?
What is this important for?
On the carboxy terminus, there is the PY motif (PPPXY) consisting of proline (P) and tyrosine (Y)
it is important in protein-protein interactions
What are the two types of cells does the collecting duct have?
principle cells for Na+ and K+ balance
intercalated cells
What is ENaC regulated by?
aldosterone
What are two molecule defects/ diseases that come from ENaC?
Liddle’s syndrome
Pseudohypoaldosteronism Type I
Explain Liddle’s syndrom
This is a gain of function mutation due to mutations of the COOH termini of β and γ subunits. There are too man channels and therefore too much Na+ is reabsorbed.
Explain Pseudohypoaldosteronism Type I
This is a loss of function due to a mutation of the NH2 terminus of the α subunit. There are too few channels and therefore not enough Na+ is reabsorbed.
