structure and function of the renal tubule Flashcards
reabsorption
when the direction of movement is from the tubular lumen into the peritubular capillary plasma
secretion
when the movement is in the opposite direction to reabsorption i.e. peritubular plasma into tubular lumen
for a substance to be reabsorbed from the tubule what must it first cross?
it must first cross the luminal membrane – diffuse through the cytosol – across the basolateral membrane and into the blood (transcellular transport). Vice versa for secretion
2 physiological processes involved in reabsorption
active and passive transfer
Active Transfer/Primary Active Transport:
Moving molecule/ion against conc gradient (low→high)
Operates against electrochemical gradient
Requires energy - driven by ATP
Passive Transfer:
Passive movement down concentration gradient (requires suitable route)
Active removal of one component - concentrates other components
Co-transport/Secondary Active Transport:
Movement of one substance down it’s concentration gradient - generates energy
Allows transport of another substance against it’s concentration gradient
Requires carrier protein
2 types: symport and anti-port
how do lipid substances, ions and natural substances move through the membrane?
lipid soluble substances move through lipid matrix
ions and neutral substances move through water filled protein channels
symport and antiport
Symport = transported species move in same direction e.g. Na+ - glucose
Antiport = transported species move in opposite directions e.g Na+ - H- antiport
If a substance is going down its concentration gradient passively, it can generate energy to take another substance either in the same direction (symport), or the other direction (antiport)
how does the co transport of sodium and glucose work?
because Na moves into the cell down it’s concentration gradient which creates lots of energy
this means it can pull other substances along with it - cotransport (a form of secondary active transport)
for Na to pull another substance with it needs a coupling mechanism – carrier protein
sodium glucose transport n tubule
high Na+ conc in tubular fluid, flows down its concentration gradient into cell
in this process it generates energy so it can take a molecule across its concentration gradient - glucose
Na+ and glucose move into the cell via the SGLUT-2 transporter
as glucose levels build up in the cell, it diffuses down its concentration gradient into blood via the GLUT-2 transporter
Na+ enters the blood via sodium potassium ATPase pump.
what other movement does the sodium potassium ATPase pump help with?
movement of other substances with sodium
amino acids reabsorbed (supporter)
also aids movement of H+ ions but an ANTIPORTER is used, so H+ ions are secreted into the tubular fluid and are excreted out in the urine makes the urine a bit acidic
a mutation in the gene that encodes for SGLUT 2 causes what?
get familial renal glycosuria – glucose in the urine
Patients don’t make SGLUT 2, so all the glucose that is filtered is just dumped into the urine and remains there
what are SGLUT 2 inhibitors are used to treat?
diabetes
name some techniques to investigate tubular function
- Clearance studies
- Micropuncture & Isolated Perfused Tubule
- Electrophysiological Analysis (look at notes)
- Potential measurement
- Patch clamping
Micropuncture
Direct sampling of tubular fluid in different parts of nephron
- puncture tubule
- inject viscous oil to block ends
- inject fluid for study
- sample and analyse
tubule can be divided into how many segments?
7
- PCT
- Thin Descending Limb, LoH
- Thin Ascending Limb, LoH
- Thick Ascending Limb, LoH
- Distal convoluted tubule (DCT)
- Collecting/Connecting tubule
- Medullary Collecting duct
throughout its length what is the nephron comprised of?
a single layer of epithelial cells resting on a basement membrane
2 Types of Nephron
Cortical nephron - 85%
Short LoH
Juxta-medullary nephron - 15%
Long LoH
they have different vascular systems
Juxta-medullary nephrons
long-reach loops that penetrate deep into the medulla - better at concentrating urine
long efferent arterioles extend from glomeruli to outer medulla and are divided into specialised capillaries called vasa recta - they extend downward into medulla and run in parallel with the LoH
the nephrons with the long LOH play a very crucial role in?
concentrating and diluting urine
Proximal Convoluted Tubule
directly adjacent to Bowman’s capsule
high capacity for reabsorption
special cellular characteristics:
- highly metabolic, numerous mitochondria for active transport
- extensive brush border on luminal side –> large SA area for rapid exchange
what are located in the luminal and basolateral membranes of the PCT
enzymatic and protein carriers, primary and secondary active transport systems, which together with its permeability characteristics make the PCT the major site of reabsorption of the glomerular filtrate
PCT - lysosomal enzymes
Glomerular filtrate is protein free but some small proteins (<60kD) get through
These proteins are taken up into the cell by endocytosis → degraded by lysosomal enzymes into amino acids and simple sugars, and reabsorbed into plasma
by the end of the early PCT whats been absorbed?
essentially all of the glucose and amino acids and much of the HCO3- have been reabsorbed
HCO3- is preferentially absorbed relative to what?
Cl-
where does Cl- concentration rise, and what is the effect of this?
the concentration of Cl- rises in the tubular fluid, establishing a Cl- concentration gradient from lumen to peritubular fluid
as Cl- moves passively down its concentration gradient the lumen acquires a positive electric charge relative to the peritubular fluid
Na+ moves passively along the gradient with Cl-
Fanconi’s Syndrome
all proximal tubule reabsorptive mechanisms are defective, so glucose, AA, Na+, K+ etc. are all found in the urine
how does the H2O reabsorption occur in the PCT?
Water is reabsorbed by osmosis – as the various substances are driven across they will pull water across
3 functionally distinct segments of the LoH:
Thin descending limb
Thin ascending limb
-thin epithelial cells, no brush border, few mitochondria & low metabolic activity
Thick ascending limb
-thick epithelial cells, extensive lateral intercellular folding, few microvilli, many mitochondria, high metabolic activity
the LoH has a critical role in what?
concentrating/diluting urine »adjusting rate of water secretion/absorption by creating an osmotic gradient in the medulla (tissue around the LoH)
so water is pulled out of the LoH by osmosis
what part of the LoH is permeable to water?
only the descending limb is permeable to water – the ascending limb (both thick and thin parts) is impermeable to water, but very active in reabsorbing sodium
what are loop diuretics and where do they act?
act at the thick ascending limb of the LoH to inhibit sodium, chloride and potassium reabsorption
they cause 20% of filtered Na to be excreted, by blocking Na-transport out of LoH
diuretics
allow you to pee out out increased amount of fluid for whatever reason
what does the LoH create?
an osmolarity gradient in medullary intersititum
how does the LoH create a medullary osmotic gradient?
Solutes accumulate in the renal medullary interstitium
A high solute concentration/high osmotic pressure is generated and maintained in the medullary interstitium and the tubular fluid becomes hypotonic
as we descend down into the medulla from the cortical region what happens?
we are creating a gradient around the LoH
as the collecting duct traverses the medulla what happens?
the urine gets more concentrated because water leaves duct by osmosis
why is the movement in the LoH called counter current?
because the 2 limbs are parallel to each other but the fluid in the 2 limbs are moving in opposite directions to each other (down and then up)
what is the fluid leaving the LoH like compared to how it entered?
the fluid leaving is hypo-osmotic in comparison to how it entered and the plasma
ascending limb
thin ascending limb permeable to Na & Cl
on the thick ascending limb side you have lots of sodium-potassium chloride transporters. Pump NaCl out of tubular fluid– accumulation in the intersititial tissue spaces around the LOH and in the medulla
the accumulation of solutes around in LoH and in the medulla creates what?
the osmotic gradient
what is the effect of the ascending limb causing this osmotic gradient?
water moves out of the descending limb by osmosis, so as you move down the descending limb the osmolarity increases because water is leaving, therefore all the stuff in there gets more concentrated (hairpin bend is where its most concentrated)
the ascending limb is impermeable to what?
H2O
what is the relevance of the ascending limb being impermeable to H2O?
water remains in there but salts are pumped out, so the osmolarity changes and when the fluid leaves it is hypo-osmotic in comparison to how it entered and the plasma
the thick ascending LoH reabsorbs how much of the filtered Na?
25%
how does the thick ascending LoH limb reabsorb the Na, K and Cl-?
Sodium (Na+), potassium (K+) and chloride (Cl−) ions are reabsorbed by active transport
via Na:K:2Cl cotransporter (symporter)
how do the Na, K and Cl move from the cell to the peritubular capillary when the ascending limb actively reabsorbs them?
Na is transported actively via Na-K-ATPase
K and Cl cross into the peritubular fluid passively.
what inhibits the Na:K:2Cl transporter, and what does this result in?
loop diuretics, results in inhibition of net NaCl reabsorption and increased excretion of these ions along with water
what do the loop diuretics do?
disrupt reabsorption of the ions, preventing the generation of the medullary osmotic gradient
without such a concentrated medulla, water has less of an osmotic driving force to leave the collecting duct system, ultimately resulting in increased urine production.
As K+ and Cl- move transcellularly across into the capillary, what happens?
they will build up a bit along the surrounding areas – this contributes to the formation of the medullary osmotic gradient
what does the vasa recta do?
delivers O2 and nutrients to cells of the loop of Henle
the vasa recta is permeable to both H2O and salts - what is the problem with this?
could disrupt the salt gradient established by the loop of Henle
-it avoids them by acting as a counter-current multiplier system
vasa recta and counter current
As the vasa recta descends into the renal medulla, water diffuses out into the surrounding fluids, and salts diffuse in. When the vasa recta ascends, the reverse occurs.
As a result, the concentration of salts in the vasa recta is always about the same, and the salt gradient established by the loop of Henle remains in place.
if blood flow increases in the vasa recta what happens?
solutes are washed out of the medulla and its interstitial osmolality is decreased
why is medullary blood flow in the vasa recta slow?
because it is sufficient to supply the metabolic needs of the tissue, but minimize solute loss from the medullary interstitium
-got to be at a certain sufficient rate that it will keep the gradient maintained but also deliver sufficient nutrients to keep the surrounding tissues of the LOH alive.
Distal Convoluted Tubule
2 parts
1st part (macula densa) linked to juxtaglomerular complex -comes in close contact with the afferent and efferent arteriole and becomes specialized to form the macula densa
Provides feedback control of GFR & tubular fluid flow in the same nephron
2nd part is very convoluted
Connecting Tubule
Connects end of DCT to collecting duct – mainly in outer cortex
Functions of DCT
- Solute reabsorption continues, w/out H2O reabsorption
- High Na+,K+-ATPase activity in basolateral membrane
- Very low H2O permeability
- Further dilution of tubular fluid
- ADH can exert actions
- Role to play in acid-base balance via secretion of NH3
does ADH work in the DCT or PCT?
DCT
what happens to tubular fluid in its passage through the distal convoluted tubule?
it’s further diluted
the joining of collecting tubules form what?
Collecting Ducts
-cuboidal epithelia, very few mitochondria
what 2 types of cells make up the collecting duct
Intercalated cells
-involved in acidification of urine and acid-base balance
Principal cells
-role to play in Na balance and ECF volume regulation
function of collecting duct
- Final site for processing urine
- Made very permeable to H2O by ADH
- Also permeable to urea
-the last 2 contribute o the counter-current mechanism
where is ADH made and stored?
made in hypothalamus, stored in pituitary gland
single effect of ADH?
conserve body water by reducing the loss of water in urine
what triggers ADH release from the pituitary gland?
a change in plasma osmolarity (concentration of solutes in the blood), sensed by hypothalmic osmoreceptors
what other receptors can regulate ADH secretion?
volume receptors and arterial baroreceptors
how does ADH cause its effect?
binding of AVP to V2-receptors on peritubular capillary cell stimulates the synthesis of aquaporin-2 water channel proteins and promotes cAMP-dependent trafficking of aquaporin 2 water channels to the luminal membrane of principal cells allowing back diffusion of water down its concentration gradient
production of new aquaporin 2’s is also stimulated
what does urea contribute to?
the medullary interstitial gradient
how does the urea contribute to the medullary interstitial gradient?
Urea filters freely through glomerulus and passes down the tubule. Unlike cortical collecting tubule, the medullary collecting duct is permeable to urea.
As water is reabsorbed from the CD (say in the presence of ADH) the urea is concentrated so that it moves out of the CD and is absorbed into the surrounding capillaries and also into the intersitium of the medulla where it contributes to the osmotic gradient around the LoH.
how are urea levels monitored?
BUN (blood urea nitrogen) test
if urea levels in the blood increase it shows that ADH has been activated and therefore patient is dehydrated
what substances are reabsorbed from the CD regardless of ADH being present or not?
Na+ and Cl-
what is the relevance of Na+ and Cl- being reabsorbed from the CD?
-maintains the medullary hyper-osmolarity, which facilitates the reabsorption of water in the presence of ADH
In the absence of ADH what happens to the CD?
CD becomes impermeable to water and urea
Sodium reabsorption in the CD continues, the tubular fluid become progressively more dilute in its progress along the duct
the volume of urine excreted under these conditions is potentially very large
4 major factors contributing to build up of solute concentration in renal medulla
- Active transport of Na+ and co-transport of K+ & Cl- out of thick ascending limb into medullary interstitium
- Active transport of ions from collecting ducts into medullary interstitium
- Facilitated diffusion of large amounts of urea from collecting ducts into medullary interstitium
- Very little diffusion of water from ascending limbs of tubules into medullary interstitium
Polycystic Kidney Disease (PKD)
Genetic disorder characterised by growth of numerous cysts in kidney
-Each of the cysts contains urine – urine means the cysts could get infected over time
glomerulonephritis (GN)
Inflammation of glomeruli of some or all of million nephrons in kidney
Can be primary or secondary to systemic disease like diabetes mellitus
Inherited diseases of the glomerular basement membrane
Diseases of the tubules
obstruction (reducing glomerular filtration)
Impairment of transport functions (reducing water & solute reabsorption) eg. Fanconi’s syndrome
Acquired Kidney Diseases - hypertension
Hypertension
Kidneys regulate ECF volume and hence influence blood pressure⇒compensatory mechanisms in response to high BP can lead to chronic kidney damage
Acquired Kidney Diseases - Congestive Cardiac Failure
Fall in cardiac output⇒renal hypoperfusion⇒registered as hypovolaemia, compensation results in pulmonary oedema
Acquired Kidney Diseases - Diabetic nephropathy
As a consequence of diabetes, filtering system of kidneys gets destroyed over time
Lithium treatment results in what?
acquired nephrogenic diabetes insipidus
-due to reduction of AQP2 expression
Diabetes insipidus (DI)
a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine.
name the different types of DI?
the different types of DI each have a different set of causes.
Central DI (CDI) - most common type in humans, neurological form that involves a deficiency of ADH/AVP.
Nephrogenic diabetes insipidus (NDI), due to kidney/nephron dysfunction caused by an insensitivity of the kidneys or nephrons to ADH.
