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Homeostasis > Renal physiology and body fluid homeostasis (part 2) > Flashcards

Renal physiology and body fluid homeostasis (part 2) Flashcards

1
Q

What is the principle behind osmoregulation?

A

ECF osmolality is maintained at the expense of ECF volume, unless there is a >10% decrease in ECF volume in which case the opposite becomes true.

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2
Q

Why is it important to maintain constant ECF osmolality?

A
  • ECF osmolality influences ICF volume.
  • Too high causes cells to swell.
  • Too low causes cells to shrink (crenate).
  • Swelling of the brainstem disrupts vital functions such as ventilation and may lead to death.
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3
Q

What are the main ways in which water is taken into the body?

A
  1. Drinking
  2. Eating
  3. Metabolism
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4
Q

What are the main ways in which water is lost from the body?

A
  • Insensitive (uncontrolled):
    1. Respration
    2. Sweating
    3. Defaecation
  • Sensitive (controlled): Urine
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5
Q

What are the ways in which water content in the body can be controlled?

A
  1. ADH
  2. Thirst
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6
Q

What are the different types of ADH receptors?

A
  1. V1: Causes vasoconstriction in arterioles. Low affinity, meaning that plasma [ADH] needs to be significantly high in order for the effect to take action.
  2. V2: Causes water permeability of the CD to increases, thus increasing the rate of water reabsorption from the CD. High affinity, meaning that a small change in plasma [ADH] has a significant effect.
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7
Q

What are the 2 systems controlling ADH release?

A
  1. Osmoregulatory system
  2. Circulatory system
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8
Q

What is water diuresis?

A

Transient increase in rate of urine production in response to drinking water.

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9
Q

What is the feedforward system responsible for water diuresis?

A

Drinking → GI reflex → (vagus nerve) → ↓ADH secretion → ↓[ADH] → ↓Water reabsorption

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10
Q

What is the feedback system responsible for water diuresis?

A

Drinking → ↓Plasma osmolality → Detected by osmoreceptors (in portal veins and hypothalamus) → ↓ADH secretion → ↓[ADH] → ↓Water reabsorption

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11
Q

What is the feedback system responsible for ADH release in response to low TBV?

A

Haemorrhage → ↓Blood volume → ↓MAP → HPBRs/Cardiopulmonary receptors → (vagus & glossopharyngeal nerves) → ↑ADH secretion → ↑[ADH] → ↑Water reabsorption & Vasoconstriction → ↑Blood volume

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12
Q

Where is ADH synthesised?

A
  • Magnocellular neurones (neurosecretory cells)
  • Cell bodies mostly located in the supraoptic nucleus (SON) but some are located in the paraventricular nucleus (PVN)
  • Hormone is syntheised in the cell bodies but is transported down axon and stored in axon terminals in the posterior pituitary
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13
Q

How are magnocellular neurones stimulated?

A

The magnocellular neurones are stimulated by various receptors. APs arriving at the nerve terminals cause voltage-gated Ca2+ channels to open, causing Ca2+ entry into the neurone to induce Ca2+-mediated exocytosis, stimulating ADH secretion.

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14
Q

Where are osmoreceptors mainly located?

A

OVLT (Organum Vasculosum Laminae Terminalis)

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15
Q

What is the mechanism of action of osmoreceptors?

A
  1. When ECF osmolality high, osmoreceptors shrink, resulting in activation of stretch-inactivated ion channels, resulting in higher frequencies of APs.
  2. When ECF osmolality low, osmoreceptors swell, resulting in inactivation of stretch-inactivated ion channels, resulting in lower frequencies of APs.
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16
Q

Which cells do ADH act on?

A

Principle cells of the DCT and CD

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17
Q

What is the mechanism of ADH action?

A
  1. ADH binds to V2 receptors (GPCR) on basolateral membrane of principle cells.
  2. Activation of V2 receptors causes activation of adenylate cyclase, which produces secondary messenger cAMP from ATP.
  3. cAMP activates PKA.
  4. PKA phosphorylates AQP2 (Aquaporin 2) on Ser256.
  5. This induces vesicles containing AQP2 to fuse with luminal membrane and increase its water permeability.
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18
Q

How does ADH increase urea permeability?

A

Increasing the number of UT-A2s in the apical membrane

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19
Q

What are the stimuli of thirst?

A
  1. ↑ Plasma osmotic pressure
  2. ↓ ECF volume
  3. Dry throat
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20
Q

How can ↓ECF volume stimulate thirst?

A
  1. Low ECF detected by HPBRs and cardiopulmonary receptors that decrease thirst inhibitory signals to the hypothalamus.
  2. Release of angiotensin II in renin-angiotensin response to low ECF stimulates thirst centres in the hypothalamus (through ATI receptors).
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21
Q

What is diabetes incipidus?

A

Production of large volumes of urine.

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22
Q

What causes diabetes incipidus?

A
  1. Neurogenic: Inability to produce/secrete ADH.
  2. Nephrogenic: Insensitivity of CD to ADH.
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23
Q

What are the ways in which Na+ secretion can be controlled?

A
  1. Physical
  2. Neurological
  3. Hormonal
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24
Q

What are the physical factors affacting Na+ excretion?

A
  1. Mean arterial blood pressure (pressure natriuresis)
  2. Colloid osmotic pressure
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25
Q

How does MAP affect rate of Na+ excretion?

A
  1. ↑ MAP increases blood flow in vasa recta, increasing the rate of countercurrent exchange between the blood and medulla interstitium. This results in more solutes carried away, which decreases osmolality of medullary interstitium, decreasing water reabsorption.
  2. ↑ MAP causes ↓ in number of Na-H exchangers in the luminal membrane of PCT epithelial cells, which decreases rate of Na+ reabsorption.
26
Q

How do neurological factors affect Na+ excretion?

A
  1. ↑NHE3 activity via α1-adrenoreceptors
  2. Efferent arteriolar vasoconstriction > Afferent arteriolar vasoconstriction
  3. Renin release
27
Q

What are the main hormones involved in ECF volume regulation?

A
  1. Renin-Angiotensin system
  2. Aldosterone
  3. Atrial natriuretic peptide (ANP
28
Q

What are the factors controlling renin secretion?

A
  1. Intrarenal baroreceptors: Decreased stretch of the afferent arteriolar walls due to decreased MAP promotes renin secretion.
  2. Renal sympathetic nerves: Stimulation by the renal sympathetic nerves promotes renin secretion via NAd release and β1-adrenoreceptors.
  3. Macula densa: Fall in ECF volume causes a fall in MAP and GFR, which decreases the rate of NaCl reabsorption by the macula densa. This stimulates renin secretion by juxtaglomerular cells via pathway involving the release of prostaglandins by the macula densa. Renin increases [AII], which promotes Na+ reabsorption in the PCT. This further decreases NaCl reabsorption in macula densa, which further increases renin secretion. This is a positive feedback system.
29
Q

How does renin control angiotensin II levels?

A
  1. Angiotensinogen is synthesised by the liver.
  2. Renin catalyses the conversion of angiotensinogen into angiotensin I.
  3. Angiotensin I is converted to angiotensin II (AII) by Angiotensin Converting Enzyme (ACE), which is found in the luminal surface of vascular endothelial cells (especially in pulmonary circulation).
30
Q

What are the effects of ATII?

A
  1. Stimulates NHE3, increasing Na+ reabsorption in the PCT and thus water reabsorption.
  2. Stimulates aldosterone production via AT2 receptors in the cells of the adrenal cortex.
  3. Stimulates thirst and the ‘sodium appetite’. These are the only mechanisms that serve to increase ECF as opposed to preventing further decrease.
  4. Causes vasoconstriction of the glomerular arterioles (efferent > afferent) via AT1 receptors, having the same effect of decreasing Na+ excretion as the renal sympathetic nerves.
  5. In addition, decrease blood flow in vasa recta decreases countercurrent exchange, which increases urea cycling in the inner medulla, promoting water reabsorption.
31
Q

What are the advantages of local intrartenal ATII synthesis?

A
  1. Local control via AII is much quicker than systemic control.
  2. PCT secretes AII into its lumen to create intraluminal [AII] higher than that of general circulation, so has greater effect.
32
Q

What is aldosterone release stimulated by?

A
  1. Increased plasma [AII]
  2. Increased plasma [K+]
  3. Decreased plasma [Na+]
33
Q

What are the effects of aldosterone on the kidneys?

A
  1. Promotes Na+ reabsorption.
  2. Promotes K+ excretion.
  3. Promotes H+ secretion into tubular lumen.
34
Q

What are the mechanisms of aldosterone action?

A
  1. K+ excretion is increased via a genomic effect whereby aldosterone promotes transcription of Na+/K+-ATPase and various Na+ & K+ channels in principles cells of the CD
  2. H+ secretion is increased via a non-genomic effect whereby aldosterone promotes the activity of K+/H+-ATPase.
35
Q

What are the effects of ANP on the kidneys?

A
  1. Inhibition of Na+ reabsorption from the CD by inhibition of ENaC via cGMP and PKG.
  2. Inhibition of Na+/K+-ATPase by PKG-mediated phosphorylation.
  3. Inhibition of Na= reabsorption in PCT via following pathway: ANP → Dopamine secretion → ↑cAMP → PKA → Phosphorylation (inhibition) of NHE3 + Na+/K+-ATPase.
  4. Inhibition of renin secretion from juxtaglomerular cells.
  5. Dilation of mesangial cells, increasing surface area of glomerular capillaries and increasing GFR.
  6. Inhibition of aldosterone secretion.
  7. Vasodilation of glomerular arterioles (Afferent > Efferent) → ↑Glomerular capillary pressure → ↑GFR. Also increases peritubular capillary pressure.
  8. Inhibition of ADH secretion.
36
Q

What did Ramsay et al. show in his water intake experiment?

A
  1. If OP normal but ECFV is low, thirst response reduced by 70%.
  2. If OP high but ECFV normal/high, thirst response reduced by 30%, indicating osmotic thirst dominates over ECFV inhibition.
  3. If OP low but ECFV low, thirst response is only 2% (accounted for by dry throat thirst). This indicates that OP inhibition overrides hypovolaemic thrist.
37
Q

What are the roles of Ca2+ in the body?

A
  1. Structural (in bone hydroxyapatite)
  2. Seconary messenger (in vesicle release)
  3. Stability of excitable cells (binds and cancels depolarising -ve charge on extracellular glycoproteins
38
Q

What are the dangers of hypocalcaemia?

A

Increased excitability of cells may lead to uncontrollable muscle spasms

39
Q

What are the dangers of hypercalcaemia?

A
  1. Decreases excitability of cells and may lead to muscle weakness
  2. Increases chance of kidney stone formation
40
Q

What are the strains on Ca2+ homeostasis?

A
  1. ↑ Ca2+: Diet
  2. ↓ Ca2+:
    - Bone
    - Foetus
    - Lactation
41
Q

How is Ca2+ reabsorbed in the PCT?

A
  • Paracellular by +ve PCT lumen
  • Paracellularly by solvent drag
  • Transcellularly through TRP5&6 (apical membrane) and then through NCX/PMCA (basolateral membrane)
42
Q

How is Ca2+ reabsorbed in the TaL of the LoH?

A
  • Transcellularly
  • Paracellularly
43
Q

How is Ca2+ reabsorbed in the DCT and CD?

A

Transcellularly:

  1. -ve lumen unfavourable for paracellular absorption
  2. Allows for greater control
44
Q

How is Ca2+ reabsorbed transcellularly?

A
  1. Ca2+ diffuses into the epithelial cells passively down the electrochemical gradient (created by membrane potential and concentration gradient) through TRPV5 & 6 on the luminal membrane.
  2. Ca2+ is sequestered by calbindin-D, which helps buffer intracellular [Ca2+] and thus helps maintain [Ca2+] gradient for passive diffusion.
  3. Ca2+ is actively extruded from the epithelial cells by PMCA and NCX located on the basolateral membrane.
45
Q

How is HPO4- reabsorbed?

A
  1. HPO42- is reabsorbed into the PCT epithelial cells via co-transporter proteins located on the luminal membrane (Type II a,b,c Na+/Pi transporters). These work in very similar fashion to SGLT transporters, but differ in the sense that their transport maximum (controlled by PTH) is close to filtered HPO42- load. They are involved in overflow control of HPO42-.
  2. HPO42- is pumped out of the epithelial cells into the ECF in exchange for organic anions.
46
Q

What are the hormones involved in Ca2+ homeostasis?

A
  1. Parathyroid hormone (PTH): ↑[Ca2+]
  2. 1,25-dihydroxycholecalciferol (1,25-DHCC): ↑[Ca2+]
  3. Calcitionin (CT): ↓[Ca2+]
47
Q

What is the action of Ca2+ on PTH secretion?

A

Ca2+ binds to GPCRs and inhibits PTH secretion via IP3 pathway.

48
Q

What are the effects of PTH on bones?

A
  1. Stimulates osteocytes to absorb Ca2+ from bone fluid and transfers it to bone-lining cells that subsequently secrete Ca2+ into ECF.
  2. Stimulates osteoblasts to release cytokines such as interleukin-6 and RANK ligand that subsequently stimulate osteoclasts to increase their activity.
  3. Stimulates bone-lining cells to shrink and retract, exposing the bone surface to osteoclast activity.
  4. Increased osteoclast activity results in greater rate of breakdown of bones, releasing Ca2+ into the ECF and increasing ECF [Ca2+].
49
Q

What are the effects of PTH on the kidneys?

A
  • ↑ Ca2+ reabsorption
  • ↓ HPO42- reabsorption
50
Q

How does PTH increase Ca2+ reabsorption in kidneys?

A
  1. PTH binds to PTH 1R receptors (GPCRs) on the basolateral membrane of DCT and CD epithelial cells.
  2. PTH binding causes activation of Gαs and Gαq, which subsequently stimulates PKA and PKC respectively.
  3. PKA-mediated phosphorylation of NCX increases its activity and the rate of Ca2+ reabsorption and thus increases ECF Ca2+.
51
Q

How does PTH decrease HPO42- reabsorption?

A
  1. PTH activates PKA and PKC through PTH 1R receptors.
  2. PKA and PKC phosphorylate scaffolding proteins NHERF-1, causing it to dissociate from type IIa (and IIc). This exposes them to endocytosis.
  3. Removal of HPO42- transporters decreases ECF [HPO42-]. This increases free [Ca2+] in ECF as it decreases the amount of insoluble calcium phosphate
52
Q

How is 1,25-DHCC activity controlled?

A
  • Synthesis from 25-HCC promoted by PTH, GH and prolactin.
  • Deactivation to 24,25-DHCC inhibited by PTH, GH and prolactin.
53
Q

What are the effects of 1,25-DHCC on the gut?

A
  1. Increased expression of genes coding for TRPV 5&6, and calbindin-D in gut epithelial cells, all of which promotes Ca2+ absorption.
  2. Increased activity of Ca2+-ATPase indirectly through increased [Ca2+].
  3. Increased expression of genes coding for type IIb Na+/Pi transporter to promote HPO42- absorption in the gut.
54
Q

What are the effects of 1,25-DHCC on the bones?

A
  1. The direct effects of 1, 25-DHCC is to promote bone resorption by promoting development of osteoclasts.
  2. The indirect effects of 1, 25-DHCC is to promote bone mineralisation by increasing ECF [Ca2+] and [HPO42-].
  3. Indirect effect outweighs direct effect so that 1, 25-DHCC has net effect of promoting mineralisation of bone.
55
Q

What are the effects of 1,25-DHCC on the kidneys?

A
  1. Increased expression of genes coding for TPRV 5&6, calbindin-D and NCX in epithelial cells of the DCT and CD of the kidneys, all of which promotes Ca2+ reabsorption.
  2. Increased activity of Ca2+-ATPase as a result of increased intracellular [Ca2+].
  3. Increased expression of genes coding for II Na+/Pi transporter to promote reabsorption of HPO42- in the PCT.
56
Q

What are the actions of calcitonin?

A
  1. Inhibits activity of osteoclasts via cAMP pathway, decreasing rate of bone demineralisation and decreasing ECF [Ca2+].
  2. Prevents excess bone demineralisation during pregnancy and lactation and promotes 1, 25-DHCC activity to provide required Ca2+ by absorption from the gut.
57
Q

What are the common causes of hypocalacemia?

A
  1. Hypoparathyroidism: Decreased PTH secretion
  2. 1,25-DHCC deficiency: Usually due to vitamin D deficinency (leading to rickets and osteomalatia)
58
Q

What are the signs and symptoms of hypocalacemia?

A
  1. Trousseau’s sign: Sustained wrist spasms.
  2. Chvostek’s sign: Contraction of facial muscles.
  3. Long QT syndrome.
  4. Insufficient bone mineralisation.
  5. Death by asphyxiation due to uncontrolled contractions of respiratory muscles.
59
Q

What are the common causes of hypercalcaemia?

A

Hyperparathyroidism

60
Q

What are the signs and symptoms of hypercalcaemia?

A
  1. Muscle weakness
  2. Reduced CNS activity
  3. Increased chance of kidney stone formation
61
Q

What are the different types of hyperparathyroidism?

A
  1. Primary: Due to cancer of the parathyroid glands.
  2. Secondary: Due to inability for target organs like kidneys to respond, resulting in broken negative feedback and thus over-production of PTH.

Homeostasis (15 decks)

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