Gene Models and Nephron Function 1 - 3 Flashcards
urine pathway
blood in through afferent arteriole
into glomerular capillaries
glomerular filtration - % of plasma moved from capillary into bowmanns capsule, whatever isnt leaves via efferent arteriole then into peritubular capillaries and into venous blood
ultrafiltrate moves through nephron and secretes urine
filtration
glomerulus 125ml/min filters plasma 180L/day permits - H2O and small mol restricts - blood cells and proteins
ultrafilrate consists of…
protein free plasma
1% filtered protein (albumin), reabsorbed by proximal tubule, doesnt appear in urine
tubular transport
apical = lumen of tubule
basolateral = peritubular capillary
transcellular reab - apical to baso, using specific transport proteins
transcellular secretion - baso to apical, lost in urine
paracellular secretion or reab - between cells, tight junctions, lets ion, solutes and water through
genes and transport
human genome = 33,000 genes
several hundred renal genes
knockout and transgenic mouse models
inherited renal disease symptoms
proximal tubule
protein free ultrafiltrate
bulk reab - 70% filtrate
contains lots of mitochondria - needs ATP to reabsorb
proximal tubule ion channels
basolateral membrane
Na/K ATPase - primary transport protein, hydrolyses ATP to move 3Na out and 2K in, also keeps intra cell [Na] low, so high extra cell and creates gradient
K channel - sets up driving force for Na uptake at apical mem, key for setting -ve mem pot
proximal tubule ion channels
apical membrane
SGLT1/2 - Na/glucose proteins, brings Na into cell, creates electrochemical driving force, uses Na to also bring in glucose which will leave at basolateral
NaPi2 - NA/phos transporter, uses Na to bring phos too, important role in ability to retain phosphate for bone formation etc
NaPi2 knockout
mouse cant make protein for transporter
lose ability to reab across apical mem
= less Pi reab
= more loss in urine
= issues in renal mineralisation
= cant maintain normal plasma phosphate level
= precipitates with calcium = kidney stones
proximal tubule
bicarbonate reabsorption
NHE3 - Na/H exchanger on apical mem, as Na enters, H leaves and binds with HCO3 to form H2CO3
carbonic anhydrase sits on apical membrane on extra cell surface causing H2CO3 to dissociate into CO2 and H2O
CO2 is freely permeable and diffuses down conc grad into cell
H2O moves in via aquaporins, down gradient
H2CO3 in cell dissociates, HCO3 and Na leave via Na/bicarb transporter on baso mem
critical in regulating plasma pH
renal NHE3 knockout
cant secrete H so cant reab HCO3
= acidosis
inhbiition of H secretion = inhibits Na and HCO3 transport = fall in fluid reab = drop in plasma HCO3 = pHfalls due to HCO3 compensation
trasnport maximum of glucose
substances reab via membrane carriers e.g. glucose and amino acids
inc plasma glucose = inc rate of filtration - glucose is freely filtered
up to renal threshold, everything filtered is reabsorbed = nothing in urine
then reaches transport maximum Tm (375mg/min) = all proteins are busy
after this you begin to see glucose in urine - important threshold for diabetes
secretion by proximal tubule - 2 systems
organic cations/anions
rapid removal
removal of plasma protein bound substances
foreign compounds e.g. penicillin - need much higher dose than you think
loop of henle
concentrates urine reabs Na, Cl, Mg, Ca and water site of action for loop diruetics thin descending limb - water out thin ascending limb - Na and Cl out thick ascending limb - Na and Cl out
thick ascending limb
Na/K ATPase and K channels - same as proximal tubule = setting -ve mem pot and low intracell Na sets driving force for Na influx at apical mem
Na, K and 2 x Cl co transport protein on baso mem uses electrical driving force for influx of Na to bring in 2 x Cl and K, Na leaves via ATPase, Cl accumulates in cell
allows Cl to move down gradient and leave cell, net reab Na/Cl creates driving force for transport of H2O in other segments - sets up osmotic gradient
protein classed as beta subunit (accessory) - regulates a transport protein, CLCK (in baso) only works when barttin is present
recycles K coming in, outer medullary potassium helps set -ve mem pot on apical mem and allows K to recycle - essential for normal function of thick ascending limb
if K levels in tubular fluid arent high enough, NKCC2 wont work
absorption of Na/Cl drives absorption of Ca/Mg - paracellular transport
Bartters syndrome
genetic inheritance, reccessive, loss of function mutations: NKCC2 mutation = no NaCl reab
salt wasting - losing too much Na/Cl in urine
polyuria = inc urine flow rate - H2O follows Nacl
dec in ECF vol = hypotension (low BP)
hypokalemia = low K in plasma
metabolic alkalosis = inc pH, too alkaline
hypercalciuria = too much Ca in urine
nephrocalcinosis = kidney stones
Cl cant leave through CLCK, if [cl] too high in cell, it stops NKCC2 from transporting: no NaCl reab
Barttin = CLCK cant work
ROMK = stops K recycling so tubular fluid K too low, cant support function of NKCC2
ROMK knockout
fractional excretion (FE) = amount in urine/amount filtered
100% = all filtered - excreted
<100% = some reab
>100% = some secreted
compare wildtype to knockout, differences in FE = tubular defect
loop diuretics
furosemide - inhibit NKCC2 so inhibit NaCl reab - lose in urine, so inhibits H20 reab
bumetanide - used for excess ECF vol = higher urine flow rate
treats high bp
side effects - Bartters like symptoms e.g. plasma K, pH, Ca
barters protection
early distal tubule
reab Na, Cl reab Mg sensitive to thiazide diuretics NCC in apical mem - Na, Cl, co transport protein Mg loss pathway unknown
Gitelmans syndrome
inherited, recessive salt wasting and polyuria hypotension hypokalaemia metabolic alkalosis hypocalciuria - very litte Ca in urine mutation in NCC = loss of func, no Na Cl reab = salt wasting, hypotension
mouse mutations and transport
xenopus oocyte studies
inject RNA of protein were interested in
oocyte processes it as normal
if a transport protein - it moves it to membrane = can do functional analysis
put radioactive Na outside oocyte, see how much ends up inside
thiazide diuretics
early distal tubule
block NaCL co transport protein
treats inc bp
side effects = gitelmans like symptoms
protection from hypertension
mutation in ROMK/NCC - gitelmans
mutation in NKCC2 - bartters
late distal
links to connecting tubules (links late distal to cortical) ——> cortical collecting ducts
- conc of urine
- reab Na and H2O
- secretion of K and H
late distal and cortical collecting ducts cell types
2 mixed types
principle - Na/H2O reab, K and H2O secretion
intercalated - alpha IC and beta IC - dynamic, shifts depending on body needs, H secretion and reab, HCO3 reab and secretion
principle cells
apical
ENaC - regulates Na absorption, epithelium channel
ROMK - K lost in urine - hypokalemia
aquaporin 2 - rate limiting step, water channel, H20 goes down osmotic gradient
principle cells
baso membrane
Kir2.3 - driving force for Na influx with Na/K pump
AQP3/4 - constiutively active
inc Na in cell = inc H secreted = high pH
dieseases with principle cells
diabetes insipidus - AQP2 issues, cant reab H2O = lost in urine
liddles syndrome - ENaC mutation = hypertension
pseudohypoaldosteronism - aldosterone = hormone
amiloride
potassium sparing diuretic, agonist of ENaC - blocks net reab of Na = blocks reab H2O = loss of gradient so K doesnt leave cell into urine
- inc urine production
- treatment for hypertension
alpha intercalated cells
apical = proton pump, H secreted to urine baso = AE1 - HCO3, Cl exchanger (anion exchanger 1)
beta intercalated cells
flipped version on alpha
apical = AE1, anions secrete into tubular fluid and lost in urine
baso = proton pump for reab of H, Cl channel for net reab of Cl
medullary collecting duct
low Na permability
high H2O and urea permeability in presence of vasopressin
acute renal failure
reversible fall in GFR over hrs/days causes = pre renal, renal and post renal impaired fliud and electrolyte homeostasis accumulation of nitrogenous waste lasts 1 week treatment = dialysis
general symptoms of acute renal failure
hypervolaemia - low ECF vol, oliguria due to low GFR
hyperkalemia - lack of K secretion
cardiac excitability - sits closer to threshold of action potential
acidosis - H accumulation as not lost in urine, depression of CNS
high urea/creatinine - impaired mental function, nausea
oliguria
fall in GFR
e.g. car accident - crushed muscles = intracell contents released = K higher in cell = released due to pressure change
oliguria
pre renal
perfusion
poor renal perfusion due to hypotension
oliguria
renal cause
rhabdomyolysis (release of myoglobin from damaged muscle) - toxic effect on tubules
high K - lack secretion and release from damaged cells - tachycardia
low HCO3 = acidosis
treatment of oliguria
IV saline - dilutes K in plasma - treats hyperkalemia
HCO3 - bring level to normal
dialysis if oliguria persists
