Osmolarity and sodium

Question 1

Define osmolarity

Answer 1

The concentration of solutes per L of fluid dissolve in

Question 2

What is volume regulated by?

What is osmolarity regulated by?

Answer 2

Volume - changing NaCl excretion

Osmolarity - change water excretion through modulating water permeability

Question 3

Review the general renal handling of Na+ and water

Answer 3

OneNote figure of a nephron
- ~2/3 of Na+ reabsorption occurs within the PT by coupling to substances such as glucose, AAs etc. on specific co-transporters
At the thick ascending limb, Na+ reabsorption is coupled to K+ and Cl- reabsorption through the NKCC2 transporter – this reabsorption occurs without the reabsorption of water as the epithelia are tight and impermeable
The remaining Na+ can be reabsorbed in the DCT through NKCC2 and in the CD by ENaC
The movement of Na+ into the medullary space creates a hypertonic medulla, causing water to leave the descending limb of the LoH
Finally, more water can be reabsorbed in the CD under homeostatic regulation (as will be discussed)

Question 4

What is the direct effect of AII on Na+ reabsorption itself

Answer 4

Binds to ATII receptor on the PT → increased activity of apical NHE3 (1 Na+ in and 1 H+ out)

Question 5

Describe stimulation and process of aldosterone secretion

Answer 5

AII binds to ATII type I receptors on these cells (Gαq-coupled) → cleavage of PIP2 into IP3 and DAG → raise [Ca2+]i by IP3 binding to IP3 receptors in intracellular stores
This intracellular Ca2+ activates the enzymes 20,22-desmolase + aldosterone synthase → aldosterone production

Question 6

What does aldosterone do?

Answer 6

Acts on cells of the late DCT and the proximal part of the CD to increase Na+ reabsorption
- binds to intracellular mineralocorticod Rs → complex acts as a TF to upregulate the production of apical ENaC and alpha and beta units of Na+/K+-ATPase
Increases Na+ reabsorption and water follows to increase the ECV

Question 7

Where is ADH secreted from?

Answer 7

Posterior pituitary

Question 8

What does ADH do in the CD?

Answer 8

• binds basolateral V2 Rs (G alpha) → PKA → phosphorylates elements of the cytoskeleton → fusion of sub-apical vesicles containing
  APQ2 with apical membrane
• water can then pass into principal cells and leaave across the BL membrane via AQP3 and 4 channels

Question 9

What happens as ADH falls?

Answer 9

AQP2 channels are reinternalised - membranes becomes more impermeable to water → membrane recycling

Question 10

What is the secondary effect of ADH on the vasculature?

Answer 10

Binds to Gq coupled V1 Rs → IP3 → Ca2+ release → Ca-calmodulin→ MLCK → vasoconstriction → raise blood pressure
(afferent>efferent vasoconstriction which reduces GFR through decreasing glomerular filtration pressure)

Question 11

Aside from the vasculature, what effects by ADH mediate?

Answer 11

• stimulates NKCC2 in the tAL of LOH through V1Rs (lead to phosphorylation of NKCC2 by PKA)

Question 12

What is normal osmolarity?

Answer 12

290 mOsm

Question 13

How may ANP play a role in maintenance of ECV?

Answer 13

High ECV causes overloading of the atria → stretch of atrial myocytes, causing them to release ANP
ANP primarily acts through cGMP-mediated effects to ultimately cause natriuresis + subsequently diuresis
E.g. ANP inhibits renin release from the macula densa
+ causes dilation of the afferent arterioles and constriction of the efferent arterioles to increase GFR and thus uresis

Question 14

Discuss mechanism regulating renin release

Answer 14

• occurs in response to reduced ECV
• modulated by tubuloglomerular feedback
• macula dense detects reduced GFR by detecting low NaCL levels
• A reduced GFR increases the time available for Na+ and Cl- reabsorption through NKCC2, hence reducing NaCl concentration at the macula densa
• This low NaCl concentration can cause closure of the basolateral anion channels, and so less ATP leaves the cell
• Normally this ATP is converted to adenosine which binds to A1 Rs on granular cells, inhibiting renin release

Question 15

Discuss mechanisms regulating ADH release

Answer 15

• increase in osmolarity detected by osmoreceptors in brain
• located in organum vasculosm laminae terminalis (OVLT) and subfornical organs of the brain
• relay signals to paraventricular and supraoptic nuclei of the hypothalamus → synapse with magnocellular cells whose axons project to the posterior pituitary. and release ADH to increase ECV

Question 16

How do osmoreceptors work?

Answer 16

• express TRPV channels
• these open in response to shrinkage of the cell
• positive inward current which depolarises the cell

Question 17

What does HF result from?

Answer 17

Ischaemic damage = reduction in contractiilty → reduction in CO

lowered BP → SNS and RAAS → retention of Na+ & water → oedema

This increased work eventually results in a reduced CO as a result of ventricular remodelling

Question 18

What may diuretics be used for?

Answer 18

Reduction of oedema (cerebral oedema)
Cardiac failure
Hypertension

Question 19

Example of a loop diuretic

Answer 19

Furosemide

Question 20

What do loop diuretics do?

Answer 20

Inhibit NKCC2 in thick ascending loop - less water and sodium reabsorbed

Question 21

Side effects of loop diuretics

Answer 21

• excessive Na+ and water loss
• K+ loss → hypokalemia → muscle weakness
• H+ loss → metabolic acidosis
• Ca2+ and Mg2+ loss
• Secondary hyperaldosteronism

Question 22

Examples of thiazide diuretics

Answer 22

Hydrochlorothiazide

Question 23

Describe thiazide diuretics

Answer 23

Binds Cl- site of the Na+/Cl- cotransporter → decreasing Na and Cl reabsorption and water too
- there is still K+ loss

Question 24

Describe by hypokalemia may occur with certain diuretics

Answer 24

Increase delivery of Na+ to the distal nephron → increases Na reabsorption through the ENaC
More K+ (and H+) leaks back into the lumen because the lumen is more negative

Question 25

Where do K+-sparing diuretics act?

Answer 25

Late distal tubule and collecting duct

Question 26

What are the two types of K+ sparing diuretic? Give examples

Answer 26

Aldosterone antagonists (spironolactone)
ENaC channel blockers (amiloride)

Question 27

Describe carbonic anhydrase inhibitors

Answer 27

Act at PCT to impare Na+, HCO3- and water reabsorption, increasing distal delivery to Na+ to the distal collecting duct and increasing loss of K+

Question 28

Describe osmotic diuretics with an example

Answer 28

Mannitol
Freely filtered at the glomerulus so generate a large osmotic potential into the lumen of the PCT, opposing osmotic gradient for paracellular absorption of water

Question 29

Why are loop diuretics more efficacious than those acting act the distal tubule?

Answer 29

In the nephron, 60-70% of Na+ is reabsorbed in the PCT; around 25% of Na+ is actively reabsorbed via the Na+/K+/2Cl- symporter in the thick ascending limb of the loop of Henle; about 5% of Na+ is reabsorbed in the DCT by the Na+/Cl- symporter; and finally around 1-2% of Na+ is reabsorbed in the collecting duct by the Na+-K+/H+ exchanger. Along the tubule, wherever Na+ is reabsorbed, water is reabsorbed too. This means that loop diuretics are the most powerful diuretics, because they can cause the excretion of 15-25% of filtered Na+. Downstream segments of the nephron have an increasingly limited ability to reabsorb Na+, so diuretics acting on the distal tubule are much less potent, and result in a much smaller diuresis