A. CONCENTRATION OF URINE

Question 1

how does the kidney conserve water by excreting a concentrated urine (2 ways)

Answer 1

1. high osmolality in medullary interstitium created/maintained by LoH provides osmotic gradient for water reabsorption into peritubular capillaries
2. action of ADH (aka vasopressin) which increases water (and urea) permeability of collecting duct

*increased water reabsorption means less urine formation (lower volume and more concentrated)

Question 2

how does osmolality differ as you move from outer medulla to inner medulla towards pelvis of kidney

Answer 2

increases (becomes more hyper-osmotic)

Question 3

thin descending limb

Answer 3

• permeable to water
• impermeable to Na+ and Cl-

Question 4

thick ascending limb

Answer 4

• permeable to water
• impermeable to Na+, Cl-, HCO3-, Ca2+, K+

Question 5

thin ascending limb (only in long LoH)

Answer 5

• impermeable to water
• permeable top Na+, Cl-

Question 6

thick ascending limb reabsorption/secretion

Answer 6

• Na+/K+ ATPase maintains low Na+ in tubular cell
• Na+/K+/2Cl- symporter moves Na+, K+, 2Cl- across apical membrane into cell as a result of Na+ gradient
• K+ channel in apical membrane enables K+ transported via Na+/K+/2Cl- to be recycled back
• Na+/H+ antiporter in apical membrane enables Na+ reabsorption and H+ secretion, with HCO3- reabsorbed

*the lumen is slightly +ve, +10mV relative to interstitial fluid, creating an EC gradient for paracellular diffusion of cations between tight junctions

Question 7

what is the osmolality of the PCT

Answer 7

isotonic (same osmolality of plasma)

Question 8

what is the osmolality of the DCT

Answer 8

hypo-osmotic

Question 9

what process creates the hyperosmotic medullary interstitium

Answer 9

countercurrent multiplication
- active movement of NaCl via Na+-K+ ATPase and Na+/K+/ 2Cl- symporter
- creates gradient for water reabsorption from descending limb by osmosis
- urea recycling

*Countercurrent exchange, in the long peritubular capillaries (vasa recta), preserves hyperosmolality of the renal medulla

Question 10

countercurrent multiplication

Answer 10

• LoH has 2 parallel limbs with tubular fluid moving in opposite directions
• countercurrent flow “multiplies” the osmotic gradient between the tubular fluid in descending and ascending limbs, increasing osmotic gradient throughout the medulla

Question 11

role of ADH on kidneys (vasopressin)

Answer 11

• regulates volume and osmolality of urine

Question 12

low ADH levels in blood

Answer 12

• large volume of dilute urine excreted
• diuresis

Question 13

high ADH levels in blood

Answer 13

• small volume of concentrated urine excreted
• anti-diuresis

Question 14

where is ADH synthesised

Answer 14

in neuroendocrine cells with cell bodies located in hypothalamus

Question 15

where is ADH transported and stored

Answer 15

in nerve terminals in posterior pituitary

Question 16

what stimulates ADH release

Answer 16

• osmotic control: increase in body fluid osmolality
• haemodynamic control: fall in blood volume/pressure (angiotensin II, nausea, acute stress)

Question 17

what inhibits ADH release

Answer 17

• atrial natriuretic peptide released from atria
• alcohol

Question 18

ADH feedback system - osmotic control

Answer 18

1. water deficit (dehydrated) = hyperosmotic fluid
2. causes osmoreceptor cells in hypothalamus to shrink and get thirsty
3. relay signal for ADH secretion from posterior pituitary
4. ADH is transported to the kidneys and increases water permeability in late DCT & collecting duct, increasing water reabsorption
5. correction of hyperosmotic fluid

*very sensitive mechanism = a 1% change in osmolality significantly alters ADH secretion

Question 19

ADH feedback system - haemodynamic control

Answer 19

• decrease blood volume or blood pressure
• activates receptors in left atrium and large pulmonary vessels
• activates receptors in aortic arch and carotid sinus
• (baroreceptors)
• relay signal for ADH secretion from posterior pituitary
• ADH is transported to the kidneys and increases water permeability in late DCT & collecting duct
• increases blood volume and blood pressure

*less sensitive mechanism - 5-10% change in blood volume/pressure stimulates ADH secretion

Question 20

how does ADH increase water permeability

Answer 20

• ADH binds to V2 receptor (GPCR - Gs receptor)
• AC hydrolyses ATP to cAMP
• inactive PKA converted to active PKA
• protein phosphorylation of vesicles with inactive water channels (internalised AQP2) fuse with cell membrane and are now functional
• now an increase in water permeability and increased water reabsorption
• promotes insertion of aquaporin 2 water channels in apical membrane in P cells of late DCT and collecting duct

Question 21

what channels are on the basolateral membrane of P cells

Answer 21

• AQP3 and AQP4 water channels
• can’t be regulated by ADH

Question 22

what channels are on the apical membrane of P cells

Answer 22

• AQP2 water channels
• regulated by ADH
• secreted by posterior pituitary

Question 23

how much NaCl and urea in outer medulla

Answer 23

• 100% NaCl
• 0% urea

Question 24

how much NaCl and urea in inner medulla

Answer 24

• 50% NaCl
• 50% urea

Question 25

how much urea is reabsorbed in PCT

Answer 25

50%

Question 26

what part of the nephron is impermeable to urea

Answer 26

- LoH (thick ascending) and DCT so urea is carried along filtrate - urea conc increases along nephron and and other solutes reabsorbed

Question 27

what part of the nephron is permeable to urea

Answer 27

- CD - urea diffuses down conc grad and moves into interstitial fluid, increasing its hyperosmolality - some urea passes from IF into thin LoH = recycling

Question 28

how does ADH affect permeability of CD to urea

Answer 28

- increases permeability - increases activity & expression of urea UT-A transporters - more urea contributing to hyperosmolality of renal medulla

Question 29

what effect does aldosterone have on kidney

Answer 29

- reabsorption of Na+ and water - secretion of K+ - secretion of H+

Question 30

what is aldosterone secretion stimulated by

Answer 30

- angiotensin II (RAAs) - increased plasma K+ conc

Question 31

what receptors does aldosterone primarily bind to

Answer 31

nuclear receptors (intracellular) - genomic effects due to affecting gene expression

Question 32

how does aldosterone cause genomic effects

Answer 32

- diffuses across membrane as is lipophilic - binds to mineralocorticoid receptor (in cytosol or nucleus) which affects gene expression - aldosterone-included proteins like ENaC and Na+/K+ ATPase produced

Question 33

what happens when aldosterone binds to plasma membrane receptors

Answer 33

- rapid response - non-genomic effects

Question 34

how does aldosterone affect P-cells of late DCT and CD

Answer 34

- unregulated expression of Na+/K+ ATPase and ENaC - increased mRNA, increased translation, increased transporter pumps produced - increased Na+ reabsorption - increased water reabsorption (following passively) - increased K+ secretion (elimination) as more K+ moved into tubular cell

Question 35

how does aldosterone affect I-cells of late DCT and CD

Answer 35

- stimulates reabsorption of bicarbonate and K+ - secretion of H+ (through plasma membrane receptors as quick?)

Question 36

what is renin release stimulated by

Answer 36

- decreased NaCl conc in filtrate sensed by macula densa cells (low body fluid molality) - decreased BP sensed by baroreceptors (pressure sensors) in afferent arterioles (low BV and hence BP) - Beta-ARs on granular cells through SNS

Question 37

what does increased renin release cause

Answer 37

- increased angiotensin II production and aldosterone release - causes increased Na+ reabsorption and hence water retention - homeostasis!

Question 38

what is the RAAs a critical regulator of

Answer 38

- blood volume - blood pressure - fluid and electrolyte balance - systemic vascular resistance

Question 39

what patients benefit with blockade of RAAs

Answer 39

- hypertension - acute myocardial infarction - chronic heart failure - stroke - diabetic nephropathy

Question 40

what is the consequence of increased activation of RAAs

Answer 40

1. increased angiotensin II - vasoconstriction so increased BP, increased GFR (via VC of efferent arteriole) 2. increased aldosterone - increased Na+ and water reabsorption - increased BV and BP (increased GFR also) - increased K+ secretion so loss of K+ in urine = hypokalaemia - increased H+ secretion so loss of H+ in urine = metabolic alkalosis