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Title: Oxford University first year Biomedical Sciences kidney notes
Description: These are extremely thorough notes which cover all aspects of the kidney including clinical conditions (lectures were shared with medics). Concise and got me a first in first year.
Description: These are extremely thorough notes which cover all aspects of the kidney including clinical conditions (lectures were shared with medics). Concise and got me a first in first year.
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Kidney notes
Introduction to epithelial transport
The main ability that epithelial cells possess is to move solutes vectorially
...
-‐ Any region at which there is potential for infection via pathogenic invasion from the external
environment is where epithelial cells will be found
Epithelia can be catergorized according to:
1
...
Absorptive – active transport of Na drives solute and water reabsorption
...
b
...
Tight junctions:
a
...
allow solutes and water to pass into cells easily as they are low resistance
and form imperfect seals
ii
...
Specialised for bulk transport of isosmotic solution and their high water
permeability to water means water moves to collapse any gradients if ion
movement occurs
...
Apical entry of sodium via carriers
v
...
b
...
prevent any significant movement can withstand large osmotic gradients
ii
...
iii
...
iv
...
Apical entry of sodium via channels
Epithelia can sometimes possess both of these functions such as the epithelia in the proximal tubule
...
The tight junction also acts as a barrier to some extent to
certain solutes and water
...
ULTIMATLEY DEPENDS ON ACTIVE TRANSPORT OF SODOIUM AS THIS ESTABLISHES THE GRADIENTS
FOR PASSIVE MOVEMENT
• The cells are asymmetrical and polarised in their structures which is important in enabling
them to carry out vectorial transport
...
It is the most fundemental asymmetrical property of epithelial cells and is the
primary reason why they can carry out vectorial transport
...
-‐ Ussing using frog skin epithelia which is ULTRA TIGHT
...
-‐ Basolateral membrane has similar properties to normal membranes:
§ Na/K ATPase
§ K leak channels
§ Low sodium permeability
§ Ca ATPase
§ Hormone receptors
§ Na/H receptor to regulate pH
-‐ Showed the apical membrane was different as it had a high sodium permeability and a
membrane potential similar to the Nernst potential of sodium
...
§ Na/glucose symport
§ Na/amino acid symport
§ Na/K/2Cl symport (provides a greater gradient for ADH to exploit to extract
water)
§ Na/H antiport
o Tight –
§ Na channels
§ Regulated tightly by aldosterone
§ Inhibited by amiloride
These create electrochemical osmotic gradients which indirectly allow for the secondary passive
movement via the paracellular route of water and solutes
...
There is no net gain of potassium as it is moved back into the cell by the Na/K ATPase pump
...
Eg: glucose-‐sodium symport, Na/H antiport, phosphate symport
...
Ds:
-‐ due to K Nernst potential and Na Nernst potential -‐-‐-‐à can be altered by changing conc of K
and Na
-‐ Na/K pump is electrogenic and impacts on the PD of the basolateral membrane but very
little contribution as limited transport as slow and saturated quickly
...
In tight epithelia P
...
D apical + P
...
-‐ Gradient drives entry of Cl on Na/K/Cl symport down concentration gradient to accumulate
into the lumen through Cl channels which are faulty in cystic fibrosis
...
d therefore Na are driven passively
mostly through the paracellular pathway into the lumen also
...
§ Increasingly tight epithelia – fine tuned regulated reabsorption –
collecting duct
The renal corpsule structure and function:
§ Bowmans capsule
§ Knot of capillaries – glomerulus
o Resin cast technique can be used to visualize capillaries
o High water permeability
o Low permeability to proteins
o High hydrostatic pressure – 45mmHg higher than normal capillaries and generated
by differential constriction of afferent and efferent arterioles
...
Extremley important
for retention of protein in plasma as damage results in presence of proteins in urine
– proteinuria
o Podocytes –
§ Also negatively charged
§ have foot processes which wrap around so projections interdigitate
§ arrangement of projections from podocytes on opposite sides forms letter
box type structure called a slit pore
§ Further interdigitations and proteins sit between adjacent foot processes
§ Negatively charged mesh formed from nephirn protein molecules which sit
inbetween
...
§ Macula densa:
o End of proximal tubule containing filtrate which comes back to touch the afferent
and efferent arterioles and monitors fluid being sent down primary tubule and
feedsback to the glomerulus – this is tubulo-‐glomeruluar feedback
Permselectivity:
-‐ Size:
o max = weight -‐ 68kDa and radius -‐ 4nm
-‐
-‐
Shape
o Hb and albumin similar molecular weight but due to letterbox type structure formed
by foot processes Hb is more readily filtered
...
o Evidence: dextrans – anionic, cationic and neutral and different sizes
Ultrafiltration
-‐ Starling forces same as elsewhere in vasculature
Net filtration pressure:
= Pressure out – pressure in
= (PGC + TTBS) – (PBS – TTGC)
*PGC -‐ pressure capillary
*forces contributing to filtration
o Due to differential constriction of efferent and afferent arteriole
TTBS – Oncotic pressure bowmans space (osmotic pressure exerted by proteins as only difference in composition is proteins)
o Effectively 0 as proteins excluded from filtrate
PBS – hydrostatic pressure bowmans space
o Remains low due to proximal capsule being continuous with the bowmans capsule
an increase in pressure in the bowmans capsule is not seen as continuous drainage
of the filtrate occurs as it is not a finite space like intracellular space in other
vasculature
...
Filtration only occurs if pressure out exceeds pressure in thus depends on:
1
...
Removal of filtrate to proximal tubule
...
-‐ Wistal rat has unique kidney architecture and is thus not representative
Formation of filtrate (GFR) = Kf x Net filtration pressure
= surface area x permeability x net filtration pressure
PGC is the most important variable – increase in P = increase in GFR:
Diameter and resistance of afferent and efferent arterioles controlled by:
o sympathetic NS
o Angiotensin II
o Tuboglumerular feedback
-‐ If ureter is obstructed then PBS may increase
-‐ Contraction of mesangial cells can alter surface area to alter Kf and therefore GFR
Autoregulation to control GFR
GFR is a 1/5TH of renal blood flow
...
Myogenic bayliss mechanism:
a
...
2
...
Macula densa in jugular glomerulus apparatus detects distal flow rate by sensing
K/Na concentrations
...
If increase in flow rate, thought adenosine is released which is hydrolysed from ATP
c
...
Measuring GFR by clearance
Clearence = volume of plasma from which a substance is completely removed
Idealistic as never is all of a substance removed from the plasma as its passes through the
glomerulus:
Therefore clearance is minimum volume of plasma which could have contained filtered substance e
...
If the marker is reabsorbed, urine
conc of S will be lower and therefore so will the clearance and GRF
...
When dehydrated ADH stimulates reabsorption of urea to act as an osmotic pull therefore
urea U value is much lower and so is GRF reading
...
The proximal tubule and tubular transport
In the collecting duct we want fluid present which is appropriate to maintain homeostasis in order to
maintain the correct plasma pH, osmarilty and circularting blood volume – this is achieved by
selective reabsorption and tubular transport
Why filter and then reabsorb so much:
1
...
2
...
3
...
4
...
In effect Na absorption allows other
solutes to ‘piggy back’
...
Structure of proximal tubule:
-‐ Brush border microvilli on luminal apical membrane to increase surface area
-‐ One cell type with three subdivision
o S1 – convulated tubule
o S2 – convulated tubule
o S3 – straight part of tubule which carries onto the loop of henle
-‐ Leaky epithelium
o High ion permability which means the apical membrane has a low potential
difference acting as a shunt and is opposite to tight epithelia of collecting duct
o High water permability – high number of aquaporins
-‐ Reabsorbs
-‐
o All filtered organic solutes
o 2/3rds of NaCl and water isotonically – it appears to absorb isotonically because
the water permeability is so high such that very small undetectable gradients can
drive a large amount of water thus it appears isotonic as the gradients and the
osmotic differences are so small
Active Na transport underlies transport with most of it being coupled to the abosorption of
most solutes, organic and water
...
Mechanism by which reabsorption occurs:
§ Can be divided into two phases:
1
...
Organic solutes, amino acids and glucose uptake
b
...
HCO3 transport
2
...
Cl-‐ transport
Glucose rebsorption mechanism:
1
...
Glucose secondary transport coupled with sodium gradient from lumen on sodium-‐glucose
transporter in apical membrane
3
...
There are two isoforms of the sodium-‐glucose transporter which are sterospecific for D
glucose:
a
...
SGLT1 in S3 which transports 2Na: 1 glucose – acts as a booster
5
...
Reabsorption rate plateaus when all the transporters are saturated
7
...
Similar manner to glucose reabsorption
2
...
Basic cationic amino acids
b
...
Neutral amino acids
d
...
It is known that specific transporters are required because inherited defects in them have
been identified with the predisposition to forming kidney stones, cystinuria, being caused
by a defect in the cationic amino acid absorption pathway
Mechanism of HCO3-‐ reabsorption from the lumen into the cell
1
...
H present in cell from dissociation of carbonic acid which has formed as a result of the entry
of carbon dioxide into the cell
3
...
The hydrogen ions react with the HCO3 in the lumen to form carbonic acid
5
...
CO2 enters cell and dissociates into hydrogen and HCO3 again catalysed by carbonic
anhydrase
7
...
Na-‐HCO3 symport on BL membrane 3HCO3: 1Na – this moves Na against its
electrochemical gradient and energy for this is obtained from the HCO3 gradient as
the stoicheomistry is 3HCO3: 1Na
b
...
The hydrogen ions are cycled around the membrane with no net loss or gain of them
Chloride reabsorption m echanism:
Occurs in second part of the tubule and is somewhat d elayed as the CORRECT CIRCUMSTANCES
need to be established by the movement of other solutes in order for it to take place
...
Paracellular – via tight junctions and lateral intercellular space which is the
passive movement down an electrochemical gradient
o 2
...
Na gradient established by Na ATPase
2
...
Hydrogen ions reacts in the lumen with the anion formate rather than HCO3 as it h as been
reabsorbed to form formic acid
4
...
Formic acid dissociates to form formate and H and formate acculmulates in the cell
6
...
Cl in cell is then transported directly into the blood via the K/Cl symport
Calcium reabsorption mechanism
1
...
Occurs once electrochemical gradients have been established in the S3 part of the proximal
tubule like with Cl
3
...
ECaC transporter on apical membrane transports Ca into cell down its electrochemical
gradient into the cell
5
...
H/Na exchanger requires ATP and p umps in 2H in for each Ca out of the cell
7
...
Mechanism of phosphate reabsorption:
1
...
Na/HPO4 2– transporter on apical membrane so 3Na+ for every HPO4 2-‐ : variable
stoichetromy depending on phosphate species but always a NET +1 charge so if H2PO2-‐ is
being transported into the cell 3Na+ ions will be transported out
...
HPO4-‐ transporter on BL membrane
Secretion of organic anions (PAH – para-‐amino hipppurate)
1
...
Na/DC2-‐ (dicarboxylate/a -‐ ketoglutarate) symporter pumps DC2-‐ in with 3Na into the cell
from the blood
3
...
The PAH is then transported out of the cell into the lumen via the anion/PAH exchanger on
the apical membrane
PAH can be used to measure renal blood flow using the clearance method
Tubular composition:
• The transepithelia potential difference changes sign along the length of the proximal tubule
due to the various reabsorptive processes
...
• In S2 the lumen is:
o positive as it Cl is being absorbed from it into the cell
o this positively drives the passive reabsorption of Na via the paracellular route as it
moves from a positive lumen to a negative cell down an electrical gradient which is
harvested to move sodium passively -‐ accounts for up to 30% of Na absorption
o Na reabsorption hardly changes along the length of the proximal tubule as almost
all solute uptake is dependent on its movement
...
Standing gradient hypothesis:
a
...
This was proposed before it was known how leaky the epithelia are -‐ Tight junctions
that define the lateral intercellular spaces are leaky and therefore there would be
BACK FLUX
2
...
The predominant anion in the tubule, Cl, is less osmotically effective than the one in
the cell, HCO3, because the tight junctions are more permeable to Cl therefore Cl
will have a less effective contribution than HCO3
Urinating concentration mechanisms:
-‐ Different components of the nephron interact in order to maintain homeostasis
-‐ Primary tubule is how we recover subsutances we didn’t want to lose to make the primary
urine
-‐ After this we want the fine tuning using the tigher epithelial components of the nephron to
reflect the simplest Ussing model
-‐ These tighter epithelia focus more so on osmoregulation and fine tweaking which is
changing the concentration and volume of urine in accordance to water balance
Water balance:
-‐ Water intake is approx 2500ml/day with 1000ml/day being lost in sweat, feces and the
airways and the remainder lost in the urine
...
§ Salt and water intake has to be uncoupled as their intake can vary independently of each
other – this is achieved by having differential specialisation in the kidneys -‐-‐à Tight
epithelia uncouple this because their water permeability is so low
§ Loop of henle is responsible for regulating the concentration of the urine and a longer loop
of Henle allows to urine to be more concentrated
Diuresis = water loss
o 20L/day
o 50mOsm/L
antidieursis = conservation of water
PLASMA OSMARILITY = 300mOsm/l
o 0
...
ADH structure:
§ 9 amino acid peptide
§ synthesised in neuroendocrine cells in the supraoptic and paraventricular nuclei of the
hypothalamus and is transported down axons to the posterior pituitary where it is stored in
the nerve terminal
§ causes the insertion of AQUAPORIN II which increases the permeability of the principle cells
of the collecting duct to water
...
Water permeability:
-‐ Water does not simply diffuse but goes via aquaporins with three isoforms which are subtly
different structures with slightly different functions:
o AQP1
§ – proximal tubule
§ Thin descending limb of loop of Henele
o AQP2
§ Apical membrane of principle collecting duct cells only when subjected to
ADH
o APQ3 and APQ4
§ Only in basolateral membrane of principle cells of collecting ducts
-‐
-‐
-‐
Osmotic water permeability in each part of the nephron is reflective of the number of
aquaporins
Once in the acending limb of the L of H there is very little water permeability
Differential permeabilities allows countercurrent multiplier to be achieved
Mechanism of ADH action
1
...
This produces cAMP due to activation of adenyl cyclase via G protein
3
...
4
...
As ADH release is stopped cAMP levels fall due to the action of phosphodiesterases
converted it to 5’AMP and endocytosis of AQP2 occurs
Diabete insipidus: very dilute urine produced
-‐ Failure of ADH release
-‐ Failure of APQ trafficking
-‐ Mutations in APQ
Countercurrent multiplication:
• Is how the osmotic gradient that ADH exploits is generated
• Experimental evidence: Kuhn and Gottschalk
o Validation for countercurrent hypothesis
§ Urine is isotonic relative to plasma in the proximal tubule regardless of final
urine osmarility
§ Urine is more concentrated at the tip of the loop of henele than in the
proximal tubule
§ Blood in the vasa recta and fluid in descending limb are isosmotic to urine
in adjacent collecting ducts at the same level of the papilla
o Countercurrent multiplier was worked out using micropuncture technique and
sampled the fluid in the renal tubule
...
o Measured osmotic pressure in 3 places: found there is an equilibrium
§ Loop of Henele
§ Collecting ducts
§ Medulla blood vessels (vasa recta)
Loop of henele:
Descending limb: uncouple salt and water transport
• Permeable to water
• Impermeable to sodium
Thin ascending limb: cells lack mitochondria and depth so insufficient ATP to pump Na
1
...
Permeable to sodium
Thick ascending limb also:
3
...
Permeable to water + ADH
2
...
Actively pumps out sodium
4
...
These are not linear events
2
...
The active transport of Na is the key stone event across the cells of the thick
ascending limb
b
...
NKCC2 (Na-‐K-‐2Cl) cotransporter in the apical membrane of ascending limb is
stimulated by ADH
...
d
...
Positive lumen electrical difference drives the paracellular reabsorption of Na
f
...
Cl/HCO3 exchanger on BL membrane – Cl pumped b ack in to cell in exchange for
HCO3 out
h
...
This single effect is inhibited by loop diurectics such as furosemide by inhibiting NKCC2
so sodium reabsorption is impaired
3
...
This is the single effect and this is m ultiplied to create the end to end gradient
5
...
Na also passively falls out of the thin ascending limb where the bend occurs due to the
movement of water out of the descending limb which increases the interstitial water
potential again
...
Makes the interstitial tissue very h ypertonic ]
8
...
2/3rds of volume is removed isotonically
§ It is essentially a snowball effect as thousands of loops of henle aligned parallel to each
other create a tremendous gradient
§ Acending and descending limbs are always trying to equilibriate resulting in a stepwise
increase in osmotic potential
§ The max transport of Na that can be achieved is at the bottom of the descending limb of the
loop where the osmarility is 1200
§ Thin ascending limb is always slightly less approx 1000 than descending because sodium is
passively lost from it so urine is a little more diluted here
...
This helps to
trap urea in the renal medulla
-‐ This is followed by the movement of water
allowing more water to b e reabsorbed
-‐ Urea efflux is mediated by UT (passive urea
transporter) which is upregulated by ADH
-‐ Urea reabsorption acts as an osmotic pull
especially when ATP is limited and Na movement
can only occur passively due to limited O2 and
Glucose
Early distal tubule role
-‐
-‐
-‐
The early distal tubule further dilutes the 100 mOsm/L tubular fluid because this segment,
like the ascending loop of Henle, actively transports sodium chloride out of the tubule but is
relatively impermeable to water
...
The fact that these large amounts of water are reabsorbed into the cortex, rather than into
the renal medulla, helps to preserve the high medullary interstitial fluid osmolarity
...
The medullary blood flow is low,
a
...
b
...
c
...
The vasa recta serve as countercurrent exchangers,
a
...
b
...
c
...
d
...
-‐
-‐
-‐
This helps to preserve the hyperosmorality of the renal medulla and without it the solute
pumped into the renal medulla would quickly dissipate
If it was simply straight down blood vessel, then the blood would leave with the solutes and
water would also be pulled out however having a change in direction prevents this washing
out of solutes
Loop of Henele:
Descending: -‐ absorbs water using water channels
Ascending:
-‐ Absorbs using carriers
o Na
o Cl
o HCO3
-‐ Via paracelluar route
o Na
o K
o Ca
o Mg
Early distal tube:
-‐ Absorbs Na, Cl using carriers
Late distal tube and collecting duct:
-‐ Absorbs:
o Na
o Water through channels
o Ureas using carriers
-‐ Secretes
o H ions using carriers
o K using channels
ACID-‐BASE REGULATION
-‐ The kidneys work with the lungs to maintain pH primarily in the:
o Proximal tubule
o Tight collecting duct
HCO3 is the fundemental buffer and the control of the excretion and reabsorption of the
HCO3 is what makes the kidneys role in acid base regulation so important
...
Must reabsorb the filtered HCO3
2
...
Both of these processes required the secretion of H+
...
Non-‐volatile acids produced:
-‐ Amino acids containing sulphur – H2S04 sulphuric acid
-‐ Cationic amino acids eg lysine – HCl – hydrochloric acid
-‐ Phosphate – H2PO4 – Phosphoric acid
HCO3 PRODUCED FROM :
1
...
ORGANIC IONS – citrate
ACID PRODUCTION DOMINATES = 70mEq/day
You need both the lungs and kidneys for pH regulation as:
1
...
pH is determined by both HCO3 and CO2 conc which is under control of both lung and
kidneys
Henderson-‐Hasselbach equation:
pH = 6
...
03 x PCO2)
The titration of HCO3 with non volatile acids forms strong sodium salts which depletes the
70mEq HCO3 from the extracellular fluid
...
Mechanism of acid excretion by the kidney:
Basic model:
From H2CO3 being acted upon by carbonic anhydrase to form H + HCO3
-‐ APICAL – H+ secretion
-‐ -‐ BASOLATERAL – HCO3
-‐ This is vital to maintain homeostasis
-‐ Kidneys :
o excrete the same amount of H+ into the lumen equivalent to the amount of
non-‐volatile acid produced that deplete the HCO3 in the ECF – 70mEq/day
non-‐volatile acid needs to be excreted
o Regenerate the HCO3 and prevent it from being excreted out –
4320mEq/day filtered that needs to be recovered
BOTH OF THESE PROCESSESS, EXCRETION OF H+ AND HCO3 REGENERATION REQUIRE THE
SECRETION OF H+ THEREFORE 70 + 4320 = 4390mEq/day H+ secreted
1
...
proximal tubule
a
...
Minimal acid elimination
c
...
There is not net movement of H+ as it is being cycled around to pick up HCO3
2
...
H+ is secreted via the Na/H exchanger into the lumen and combines with the HCO3
in the lumen to form H20 and CO2 catalysed by the membrane isoform of carbonic
anhydrase
4
...
H+ is recycled again for secretion by Na/exchanger or H+-‐ATPase
6
...
Loop of Henele
a
...
Tight epithelia of collecting duct and distal tubule
a
...
Significant acid elimination
1
...
CO2 and water enter cell from blood and combine to form H2C03 and then H+ and
HCO3 via CA
3
...
H+ is secreted via H+ ATPase into lumen – less dependent on Na gradient
a
...
SEE GRAPH
5
...
H+ instead acidifies tubular fluid or combines with a buffer:
a
...
amount available = amount filtered – amount reabsorbed
ii
...
NH3 -‐
i
...
glutamine -‐à glutamic acid catalysed by glutaminase
OR
2
...
PAH exchanged for a-‐KG
4
...
H+ is secreted from the cell via the Na/H exchange
c
...
NH3 is lipid soluble so crosses the membrane into the lumen
and is converted to charged NH4+ with the H+ secreted
2
...
3
...
NH4+ MADE IN TUBULE CELLS FROM NH3 AND H+ AND
EXCRETED VIA Na/H exchanger
b
...
These two then diffuse back into the
collecting duct where they form NH4+ and it is finally
trapped
...
This means that there can be a net gain and regeneration of HCO3 and net loss of
H+
8
...
THE DISTINCTION BETWEEN THE REGENERATION AND REABSORBTION OF HCO3 IS
DETERMINED BY WHAT HAPPENS TO THE H+ ION:
REABSORB = COMBINE WITH HCO3
REGENERATION = COMBIEN WITH BUFFER
Secretion of HCO3 by Type B intercalated cells:
-‐ Ussing model shows simply by reversing the 2 proteins on the apical and BL
membranes can the whole function of the cell change
1
...
H+ ATPase on basolateral membrane
-‐ They are few in number but increase in number when we are in an alkolitic state
such as vomiting so:
o Down regulation of H+ secretion
o Secretion of HCO3
-‐ Type A intercalated cells can be converted to type B by either
o Internal transfer of proteins
o Turnover of cells results in more committing to be type B rather than type A
K+ balance:
§ Reciprocal control between H+ and K+
§ Hyperkalemia = acidosis
o High K+ conc interferes with the enzyme glutamate dehydrogenase
preventing NH3 synthesis so less is available to buffer H+ leading to acidosis
...
Summary:
1
...
HCO3 required in body to buffer non-‐volatile acids produced
a
...
Regenerated in collecting duct type A intercalated cells
3
...
Specifically most important kidney regulation is of water and sodium which are the main
determinants of extracellular osmorality – this is important as it determines cell VOLUME changes
Extracellular fluid VOLUME and OSMORALITY are the two parameters regulated to control salt and
water balance
Levels of kidney regulation:
1
...
Physical
3
...
It also allows the kidney to maintain a relatively constant blood flow and glomerular
filtration rate (GFR) necessary for the clearance of metabolic wastes while maintaining efficient
recovery of filtered elec-‐ trolytes and nutrients by the renal tubules
...
AUTOREGULATION
Flow dependence of Na absorption – glomerulotubular balance and tubuologlomerular feedback:
When there are changes in the GFR and therefore Na load presented to the nephron the
proximal tubule reabsorbs a constant fraction of the load ~ 2/3rds which corresponds to a
smaller absolute amount
1
...
Importanat in protecting glomerular capillaries against rapid changes in pressure
b
...
Via stretch activated calcium channels mechanism
2
...
Peritubular capillary m echanism
i
...
These starling forces which favour reabsorption are:
1
...
Low Hydrostatic pressure gradients
iii
...
Tubuloglomerular feedback
a
...
Juxtaglomerular apparatus (JGA) detects the changes in sodium chloride reaching the
macula densa cells in the distal tubule
...
Adjusts the diameter of the afferent arteriole accordingly
Tubuloglomerular feedback mechanism
1
...
pressure natrieursis mechanism inhibits sodium reabsorption into the proximal tubule
3
...
This increases uptake of Na by Na-‐K-‐2Cl cotransporter in apical membrane of the macula densa
5
...
This is associated with the release of ATP from the basolateral membrane of the macula densa from
the maxi anionic channel (this is still controversial)
7
...
Mechanism by
which ATP does this is still debated:
B) CONTROL OF NA EXCRETION VIA EFFECTIVE CIRCULATING VOLUME
-‐ This refers to theportion of the extracellular fluid that is contained within the vascular
system and is essentially perfusing the tissues
-‐ Depends on:
o Na concentration (determines ECF volume)
o Pressure
o Cardiac output
o Blood pressure
-‐ For example congestive heart failure often leads to an increase in ECF volume (edema)
because:
o Sodium and water retention (paradoxical)
o Poor cardiac performance decreases cardiac output
o This causes a decrease in effective circulating volume
o The kidney retains more sodium to conteract the decrease in effective circulating
volume
Angiotensin II control:
-‐ Most powerful Na retaining hormone which causes an increase in MEAN ARTERIAL
PRESSURE (MAP)
1) Stimulates aldosterone secretion from adrenal cortex – 2% of Na filtered is under this
regulation
a
...
ENaC
ii
...
Na ATPase
b
...
this is detected by osmoreceptors stimulating ADH secretion from the posterior
pituitary which increases water reabsorption and therefore increases plasma
volume causing an increase in mean arterial pressure
i
...
Increaed expression of AQP2 and ENaC
d
...
This reduces the peritubular hydrostatic pressure so that the net tubular
reabsorption of Na from proximal tubule is increased via glomerulartubulo balance
mechanism
b
...
1
...
ANP causes the vasodilation of afferent and efferent glomerular arterioles
3
...
This decreases renin secretion
5
...
Antagonism of ADH in the collecting duct
7
...
NATRIURETIC HUMORAL FACTORS:
-‐
-‐
-‐
-‐
Inhibit Na reabsorption:
1
...
Inhibition of Na and K channels through phosphorylation:
o Prostaglandins
o Bradykinin
3
...
Decrease in vascular resistance
2
...
increase in medullary blood flow (vasa recta)
4
...
increase in sodium excretion
Na transport in proximal vs distal tubule
Proximal:
-‐ Na enters on a symporter with an organic ion
-‐ Cl only enters the blood paracellular
-‐ Na/H exchanger through which Na enters
Distal:
-‐ Na enters with Cl in Na/Cl symport
-‐ Cl enters blood via paracellular and transcelllular route
-‐ K channel on apical membrane and moves out into lumen
-‐ Na on apical membrane allowing Na to passively move in
DRUGS AND INHIBITORS:
1
...
Furosemide
b
...
Inhibit NCC
a
...
Inhibit ENaC and Na/H exchanger
a
...
If reduced blood volume
a
...
More water is retained to dissolve the Na
2
...
Drinking water
Change in Na excretion
-‐ Angiotensim II/
Aldosterone – promote
reabsorption of Na
-‐ ANP (atrial natieurtic
peptide – inhibit
reabsorption of Na
a
...
c
...
Rapid increase in urine flow
Increase in volume
Decrease in osmorality
ADH is inhibited and water is not extracted from the collecting ducts and reabsorbed
2
...
Volume expansion without a change in osmolarity
b
...
Have to wait for an increase in volume to supress the excretion of Na which will
eventually lead to a change in osmolarity and a change urine flow
d
...
Organum vasculosoum laminae terminalis (OVLT) (thirst receptors)
2
...
OVLT and SFO detect:
a
...
decreased effective circulating (Renin à angiotensin II à aldosterone etc)
2
...
Thirst results in an increase in water intake
4
...
Increased Na intake stimulated by OVLT to counteract decreased effective circulating
volume
ADH
Triggers for release:
1
...
Reduced effective ciruculating volume – Detected by atrial stretch which secretes ANP
3
...
ADH binds to V2 receptor on principle cells membrane
2
...
This activates PKA which phosphorylates the CREB protein in the nucleus and this binds to
the CREB gene
4
...
Animal model, brattlebro rats which lack ADH due to having diabetes insipidus
2
...
Without ADH there are still indentation in the membrane showing the animal retains all the
machinery just lacks the trigger that is ADH
4
...
Other actions of ADH:
1
...
Stimulates NKCC in thin ascending loop of Henele – so sodium can drain out water
3
...
Volume sensors
Cardiovasular – change in sympathetic discharge
a
...
Atrial stretch receptors
c
...
Pressure receptors in renal afferent arterioles
Renal:
a
...
Increase in Na/Cl reabsorption across the macula densa which represents an increase in
effective circulating volume:
a
...
Change in membrane potential opens up ATP channels which is hydrolysed to
Adenosine by activity of exoenzyme
c
...
Angiotensin II
3
...
ADH
5
...
Sympathetic nerve activity and catelochoamines
2
...
Angiotensinogen is released by the liver and converted to angiotensin I by renin which
shortens the angiotensinogen at Leu-‐Val and ACE which shortens at Phe-‐His
2
...
Angiotensin II travels to kidneys and stimulates:
a
...
Increased insertion of Na ATPase BLM and apical ENaC (Na channel)
ii
...
Thirst – stimulates ADH release so increased water reabsorption
c
...
Reduces hydrostatic pressure in peritubular capillaries
ii
...
Increases GFR as efferent arteriole is more constricted than the afferent –
seems contradicting as if there is a decrease in volume surely you want less
filtered however a decrease in volume means more waste that needs to be
excreted
...
Macula densa heightened sensitivity to distal flow rate:
i
...
ii
...
Measuring the GFR from the renal tubule
2
...
Seeing effects on GFR
4
...
GFR decreases as adenosine release causes efferent arteriole
dilation reducing pressure – this is a protective response
e
...
Rare example of regulation on leaky epithelia
ii
...
Increase in cAMP stimulates PKA and insertion Na/H exchanger
2
...
Increase catecholamine binding – regulate vasoconstriction and
transport events to some extent
ANP – antagonistic system
Mechanism: ANTAGONISES EFFECTS OF ANGIOTENSIN II AND ALDOSTERONE
1
...
Causes vasodilation
3
...
Na reabsorption inhibited so raises load to macula densa in distal tubule and inner
medullary collecting duct increased
5
...
ANG II and renin release inhibited
7
Title: Oxford University first year Biomedical Sciences kidney notes
Description: These are extremely thorough notes which cover all aspects of the kidney including clinical conditions (lectures were shared with medics). Concise and got me a first in first year.
Description: These are extremely thorough notes which cover all aspects of the kidney including clinical conditions (lectures were shared with medics). Concise and got me a first in first year.