Renal- control of plasma osmolariy

Question 1

How is urine concentrated

Answer 1

Very active salt transport leads to a hypertonic medulla which is used to
produce hypertonic urine.
 When aquaporin 2 is activated, water is reabsorbed in the collecting duct,
leading to concentrated urine being produced.

Question 2

Describe the loop of Henle

Answer 2

The descending limb is permeable to water but impermeable
to solutes, meaning that water moves across the tubular wall
into the medullar space, making the filtrate hypertonic.
 The ascending limb is impermeable to water (lack of
aquaporins), but permeable to solutes, leading to an efflux of
NaCl into the interstitium. This makes the interstitium
hypertonic and the tubular fluid hypotonic.

Question 3

Describe the vasa recta (medullary capillaries)

Answer 3

The vasa recta are long thin-walled vessels that parallel the
loop of Henle of the juxtamedullary nephron.
 The descending part of the vasa recta is parallel to the ascending limb of the loop of Henle and the ascending part of the vesa recta is parallel to the descending limb of the loop of
Henle.

 Descending part of vesa recta: solutes are being transported out of the
ascending limb and the solutes are then transported into the vesa recta. The
blood becomes hypertonic.

 Ascending part of vesa recta: water is being transported out of the
ascending limb which travels into the vasa recta which is hypertonic. The
blood becomes isosmotic.

Question 4

Describe the plasma concentration of ADH

Answer 4

ADH is produced by two nuclei in the hypothalamus: supraoptic nucleus and
the paraventricular nucleus.
 ADH is secreted by the posterior pituitary in response to changes in plasma
osmolarity.
 ADH secretion is caused by two mechanisms:
o Detecting plasma osmolarity (very sensitive): increased plasma
osmolarity is detected by osmoreceptors, resulting in the secretion
of ADH. Aquaporins are regulated to produce a more hypertonic
urine.
o Detecting plasma volume (less sensitive): decreased plasma volume is detected by baroreceptors. It also increases
ADH secretion.

Question 5

How is ADH secretion directly related to plasma osmolarity

Answer 5

Baseline ADH secretion at low plasma osmolarity.
 ADH secretion increases past 280 mosm/L.
 Maximum secretion of ADH at 310 mosm/L.
 Syndrome of inappropriate antidiuretic (SIADH): ADH is secreted at higher levels than normal. As a result, blood osmolarity
is kept slightly lower than what it normally should be.

Question 6

Describe the actions of ADH on the collecting duct

Answer 6

Increased water permeability of the collecting duct.
 Increased Na
+ reabsorption in TALH (not in humans).

Increased urea reabsorption in the inner medullary collecting duct. Keeps osmolarity high in the medulla as urea contributes
to 50% of osmolarity.
1. Action of ADH in collecting duct
 ADH binds to the V2 vasopressin receptor, activating
cAMP generation by adenylyl cyclase.
 This activates protein kinase A (made of 2 catalytic and
2 regulatory subunits).
 Upon binding of cAMP to the regulatory subunit, the
regulatory subunit dissociates from the protein and
releases active protein kinase A subunit which directly
phosphorylates AQP-2 channels.
 Vesicles containing AQP-2 are inserted onto the luminal
membrane, increasing the permeability of water from
the lumen into the principle cell.
 AQP-3 and AQP-4 are constituently expressed to allow transcellular water transport.

2. Maximal ADH
    At maximal ADH, the filtrate is more hypertonic meaning there is more reabsorption of salt in the thick ascending limb
   making the medulla hypertonic.
    At maximal ADH, maximum amount of water is reabsorbed from the tubular lumen (high luminal AQP-2 channel
   expression).
    Urine osmolarity is about 1.2 osmoles.
3. Minimal ADH
    Aquaporin channels are not activated.
    After passing the thick ascending limb, the filtrate has low osmolarity.
    Additional salt reabsorption in the DCT by NKCC2 salt transporter meanin. Na
   + reabsorption also via ENaC.
    Low salt reabsorption means urine osmolarity is 50 mosmol, so the urine is very dilute as there is no water exchange with
   the surroundings.

Question 7

what happens in diabetes insipidus

Answer 7

Very little water reabsorption in the collecting duct results in large volumes of dilute urine at all times. Production can be up
to 25 l of urine a day.
1. Central diabetes insipidus (lack of ADH secretion)
 Congenital absence of ADH.
 Acquired: head trauma/surgery if nerves from the hypothalamus to the pituitary are damaged, disrupting the secretion of
ADH.
 Damage to posterior pituitary: benign tumours on anterior pituitary can cause problems with the production of many
hormones. Swelling on the anterior pituitary following neurosurgical intervention leads to loss of ADH production for a few
days.
 Treated with ADH analogue nasal sprays (taken up by the mucous membrane in the nose).
 Treated with carbamazepine (long-term).
2. Nephrogenic diabetes insipidus (V2 receptor mutation)
 V2 receptor no longer detects ADH as a result of the receptor misfolding or degradation.
 Acquired: lithium therapy.
 Treated with pharmacochaperones: strong agonists of receptor which force the receptor into a specific conformation. High
affinity agonist artificially folds the misfolded proteins.

Question 8

what is SIADH and NSIAD

Answer 8

Too much water reabsorption in the collecting duct: low urine output despite marked hyponatraemia.
1. Syndrome of inappropriate ADH secretion (SIADH)
 Elderly
 Acquired: several diseases (e.g. disseminated tuberculosis), drugs.
 Treated with water restriction, CAVE rapid correction (central pontine myolinolysis).
2. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD)
 V2 receptor gain of function mutations. Receptor continually activates adenyl cyclase producing cAMP without bound
agonist.
 Treated with water restriction.

Question 9

How is urea handled in the nephrons

Answer 9

Urea makes up 50% of the osmolarity in the inner medullary interstitium.
 There is passive transport in the proximal tubule. However, urea is actively
excreted in the inner medullary collecting duct. This means that additional urea can
drive additional water retrieval under conditions of high antidiuretic hormone
secretion.

ADH increases the number of urea transporters out from the
inner medullary collecting duct.

Question 10

How is extracellular volume controlled

Answer 10

Water content (i.e. volume) of extracellular fluid is determined
by its content of osmotically active solute.
 The major solute in extracellular fluid is Na
+ and its associated
anions account for >95% of plasma osmolarity.
 PNa is normally kept fairly constant.

Question 11

Describe how sodium balance is maintained

Answer 11

Uncontrolled intake in the intestine as kidneys can
control Na
+ balance effectively.
 Uncontrolled output: through the skin by sweat, faeces.
 Find control of output is by excretion in the urine.

Question 12

What is the effective circulating volume

Answer 12

An index of the fullness of the circulatory system. Normally proportional to the extracellular
volume, but there are certain conditions where the circulating volume is decreased but the
extracellular volume is not. This leads to renal Na
+ retention and oedema: heart failure, cirrhosis
(insufficient albumin production by the liver decreases oncotic pressure leading to increased
reabsorption and less filtration (oedema)

Question 13

How is the effective circulating volume monitored

Answer 13

Arterial pressure: baroreceptors
 Venous pressure: atrial receptors
 Juxtaglomerular apparatus

Question 14

How does the body respond to changes in effective circulating volume

Answer 14

↓ arterial and/or venous pressure ↑ renal sympathetic nervous activity:
o Constricts afferent arterioles  ↓ renal blood flow  ↓ GFR  ↑ absorption.
o Stimulates reabsorption in proximal tubule and loop of Henle.
o Stimulates renin release from juxtoglomerular apparatus.
 ↑ renal sympathetic activity and ↓ renal perfusion pressure  ↑ renin secretion from juxtaglomerular apparatus.