Week 7 (kidney) physiology Flashcards
deep anaesthesia use in rodent model studies
To maintain cardiovascular stability - studying kidney function
Enables:
single nephron micropuncture - test to assess how the nephron is handling fluid.
proximal/distal tubule and peritubular capillary
Tubules have anatomical proximity to capillaries.
Efficient exchange of substances between the nephron and the bloodstream
functional imaging of kidney (normal vs hypertension)
Through MRI and contrast agents injected into the blood stream.
Healthy kidneys are generally well perfused.
Kidneys suffered from hypertension will generally undergo atrophy and are not well perfused —–> non-functional
nocturnal dip of BP (measure)
Absence of nocturnal dip exists in pre-hypertension and diabetes.
retinal imaging and hypertension
Retinal capillary/arteriole changes are indicative of some diabetic and hypertensive disorders. Such as thicker arteriole walls and loss of small capillaries.
kidney’s perfusion
Kidney take 20% of the cardiac output, thus highly perfused.
But the arterial beds of the kidney are auto-regulated.
Along with brain and heart.
Renal autoregulation of blood flow
So the glomerular filtration rate is tightly regulated within physiological ranges (AUTOREGULATORY RANGE of BP (80mmHg - 180mmHg)
Flow can be detected using?
Ultrasound probes:
By measuring the frequency difference of blood flow to measure it.
Why is autoregulation of blood flow important?
So the perfusion of the organ is stable despite acute changes in blood pressure.
myogenic reflex of renal vasculature
- As arteriole stretches -> detected by smooth muscle cells around arteriole
- The stretch releases ATP (autocrine signalling)
- Extracellular ATP is detected by P2X1 receptor —-> increase in intracellular calcium
- intracellular calcium will lead to muscle cell contraction
- arteriole constriction
sensitivity of ATP of arterioles
Amongst:
arcuate (between medulla and cortex)
interlobular (branches from arcuate arterioles)
afferent arterioles (branches from interlobular)
Afferent arterioles are the most sensitive to extracellular ATP concentration that leads to arteriole constriction.
Rodent model (P2X1 KO)
When these receptors to ATP are knocked out, there will be no myogenic reflex.
oxygen gradient in the kidney
Highest in the cortex, lowest in the medulla (10mmHg)
This means that the cells in the medulla are very vulnerable to abnormal anaemia conditions
layers of glomerular filtration (from capillary blood to primary urine)
From capillary blood:
- (Capillary) Glomerular endothelial cells
- (Connective tissue) Glomerular basement membrane
- Podocytes
To Bowman’s capsule
Glomerular endothelial cells (permeability)
- Negatively charged
- HIGH permeability
Glomerular basement membrane (permeability)
- Has collagen and laminin, HIGHLY negatively charged
Some proteins are negatively charged, repelled from basement membrane. - HIGH permeability
Podocytes (which layer is it? what is it called? function?)
- The last layer of the glomerular filtration
- This is the barrier that truly controls substances that filter through.
The cell-cell junction between foot processes of podocytes are called slit diaphragms.
another name for slit membrane/diaphragm
nephrins
Where are peritubular capillaries from?
From the efferent arteriole that continues to reabsorb substances from the renal tubules.
What is the molecular radius that all charges can pass through the glomerular filtration layers?
1.6 nm
How does charge affect protein filtration through the glomerulus
The more negatively charged, the less filterable.
The more positively charged, the more filterable.
- If the molecular radius of an anion reaches 3nm, it is not filterable at all.
For example: albumin (-ve charge and between 3-4 nm) and not filtered.
Reptation in glomerular filtration
Reptation - derived from reptile
Shape of filtered substance also matters.
nephrin vs podocin
nephrins make up the slit membrane between podocytes, regulates permeability.
podocin can interact with nephrins and act as scaffolding proteins that structurally support the slit membrane.
podocin KO consequence (mice model)
- protein leakage in urine
- decreased survival rate
mutation in podocin and nephrin
- leads to nephrotic syndrome
- leakage of proteins to the urine.
genetic mutations of the nephrons that lead to dehydration
- nephrogenic DI: irresponsive to ADH –> dilute urine
- Bartter syndrome: failure to reabsorb sodium and chloride –> excessive loss of salt and water.
What’s another mechanism of renal autoregulation aside from myogenic reflex
tubuloglomerular feedback (TGF):
The tubular cells - macula densa, and the vascular cells - afferent arteriole form the juxtaglomerular apparatus.
- Negative feedback from nephrons to afferent arteriole.
Where is the macula densa?
Distal convoluted tubule
How does the macula densa feeds back?
They sense the concentration of Chloride and Sodium ions, if in excess, they will feedback to the afferent arteriole.
—> paracrine signalling
—> constriction of the afferent arteriole.
How does concentration of chloride stimulate tubuloglomerular feedback?
The rise in Cl- concentration is sensed by apical NKCC2 (sodium-potassium-2chloride cotransporter)
Macula densa will release ATP to constrict the afferent arteriole.
What side is the apical membrane (tubule) facing?
the urine
What side is the basolateral membrane (tubule) facing?
the blood
proximal c. tubule reabsorption (iso-osmotic)
Reabsorbs the same amount of sodium as it does for water.
Osmolarity stays the same.
Fanconi syndrome characteristic
Defect in the proximal tubule where it cannot reabsorb nutrient (glucose) or electrolytes back.
causes of Fanconi syndrome
Most times drug toxicity (paracetamol, antibiotics, anti-cancer drugs)
- sometimes genetic factors.
glomerulotubular balance (GTB) is…
as GFR increases, proximal tubule reabsorption increases too.
reabsorption is in proportion to GFR.
GTB (difference from TGF)
glomerulotubular balance
vs
tubuloglomerular feedback
- There is limited reabsorption of the distal tubules
- distal tubules are more regulatory.
- not neuronal or hormonal, maybe through ATP.
Principal cell (collecting tubule) channels
ENaC - transports Na+ from urine to epithelial cell
Na/K pump - reabsorbs Na+ from the cell to the blood in exchange with K+ using ATP hydrolysis.
ROMK - transports K+ out to the urine
4 actions of aldosterone to ENaC
- (increase driving force) Increases turnover of Na+/K+ pump, much more efficiency, more Na+ chemical gradient —-> indirectly stimulates ENaC to reabsorb Na+ from urine.
- (makes more channel) via MR, stimulates transcription of 3 subunits that make up ENaC.
- quicker transportation of ENaC to the apical membrane (SGK1).
- suppresses degradation (ubiquitin ligases)
Increases K+ secretion.
SGK1 function
transport ENaC to apical surface of tubule
what kind of transporter is ENaC
ion channel - passive diffusion of sodium
full name of ENaC
epithelial sodium channel
Amiloride is??
Is an anti-hypertensive drug.
Blocks ENaC. So it increases Na+ excretion and retains K+.
Na+ influx causes…
What can resume Na+ influx?
- The influx of positive charge will reduce the electrochemical gradient for Na+ to come in.
- Positive charge needs to go out for Na+ influx,
- K+ goes out.
What if the renal cell doesn’t have 11beta-HSD2?
Glucocorticoid, cortisol, will stimulate MR too, therefore there will be
Overactivation of ENaC from MR stimulation.
1. Hypertension.
2. Low sodium excretion
3. Much more responsive to amiloride (inhibitor of ENaC)
function of 11beta-HSD2
turns cortisol to cortisone.
Why does 11beta-HSD2 dysfunction lead to death?
Not from hypertension.
It’s from increased loss of potassium –> increased excitability – heart attack.
Another mechanism that copes with high BP
pressure natriuresis
health vs hypertensive people in excretion of sodium (high BP)
hypertensive people are less able to excrete sodium through the renal pathway to decrease BP.
Pressure natriuresis: pathways
Increase in BP: aorta or renal artery pressure.
- reduction in tubular Na+ reabsorption
- an increase in urine Na excretion (natriuresis)
How do kidneys detect high BP when it can autoregulate?
Cortex blood flow remains constant.
- GFR remains constant
Medullary flow increases as blood flow increases. (medulla doesn’t autoregulate)
- limited space in the renal capsule –> increased Medullary flow will lead to higher hydrostatic pressure.
- downregulates epithelial sodium transporters.
how high BP regulates transporters
Increase flow or BP:
downregulate NHE (Na+/H+ exchange) and NKCC2 (Na/K/2Cl cotransporter).
- internalise NHE
- increased sodium excretion
ATP role in pressure-natriuresis
stretch of afferent arteriole –> release of ATP
- ATP will downregulate NHE3 and NKCC2.
-> increased sodium excretion and relieve hypertension
NO role in pressure-natriuresis
- downregulates NKCC2 like ATP does.
- vasodilates -> increased hydrostatic pressure to reduce Na+ reabsorption (proximal tubule) and increase natriuresis
- Thick limb of Henle (Ca2+ influx - increase in NO): downregulate NKCC2 and Na+\K+ pump.
