Structure & Function of Renal Tubule Flashcards
What occurs in the Bowman’s Capsule and glomerulus?
Filters large amounts of plasma
What occurs in the segments of the renal tubule?
Filtered fluid is converted to urine
Explain the composition of GF compared to plasma
GF = same composition as plasma except has no cells and v. little protein
BUT composition of urine ≠ plasma (and GF)
What rate is GF formed at?
GF formed at 120 ml/min
When does urine formation begin?
when large amounts of fluid (virtually protein free) is filtered from the glomerular capillaries → Bowman’s capsule
What is GF?
GF is an ultrafiltrate of plasma
What happens to the filtrate as it travels along the tubule?
There is selective modification of filtrate as it passes through tubule
How is the filtrate modified along the tubule?
Modified by process of reabsorption and secretion of water / various solutes
Modification done by tubular transport of solutes and water into and out of tubule
What is Polycystic Kidney Disease (PKD)?
Genetic disorder characterised by the growth of numerous cysts in the kidney
What are the diseases of the glomerulus?
Usually called 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
Describe the diseases of the tubules
obstruction (reducing GFR)
Impairment of transport functions (reducing water & solute reabsorption) eg. Fanconi’s syndrome
How does hypertension affect the kidneys
Kidneys regulate ECF volume; influence BP ⇒ compensatory mechanisms responding to high BP can lead to chronic kidney damage
How does congenitive cardiac failure affect the kidneys?
Fall in CO ⇒ renal hypoperfusion ⇒ registered as hypovolaemia, compensation results in pulmonary oedema
What is diabetic nephropathy?
As a consequence of diabetes, filtering system of kidneys gets destroyed over time
How does lithium treatment affect the kidneys?
Lithium treatment results in acquired nephrogenic diabetes insipidus due to reduction of AQP2 expression
Explain what is meant by reabsorption in the kidneys
Fluid movement from
Tubular lumen → peritubular capillary = reabsorption
Describe the movement of fluid during secretion in the kidneys
peritubular plasma→ tubular lumen = secretion
What is the purpose of creating a glomerulur filtrate?
Clearing unwanted substances by excretion into urine & Returning wanted substances by reabsorption into blood
What is active transfer/transport ?
Moving molecule/ion against conc gradient (low→high)
Operates against electrochemical gradient
Requires energy - driven by ATP
What is passive transfer?
Passive movement down concentration gradient (requires suitable route)
Active removal of one component concentrates other components
* can generate energy -> co-transport
What is co-transport (secondary active transport)?
Movement of one substance down its [ ] gradient generates energy
Allows transport of another substance against its [ ] gradient
Requires carrier protein
What are the 2 types of Co-transport?
symport and antiport
What is a symport?
Symport = transported species move in same direction e.g. Na+-glucose
What is an antiport?
Antiport = transported species move in opposite directions e.g Na+-H- antiport
What type of transport occurs in tubules?
Combination of active & passive mechanisms ⇒
transcellular transport over luminal & basolateral membranes (either direction)
Explain how movement in tubules occurs?
- High [Na] in tubule (140mEq/L)
- low [Na] (12mEq/L) inside cell
- ∴ Na moves down conc gradient at luminal membrane aided by greater intracellular negative potential (-70mv)
How is glucose transported into cells through tubules?
As Na diffuses down electrochemical gradient, energy is released driving glucose against its concentration gradient across luminal membrane → cells
(Na-glucose symport via a specific carrier protein)
Where is energy generates from to allow glucose transport?
Energy generated from Na moving into cell is generated by primary active transport of Na out of the cell at the basolateral membrane
What is the role of the Na/K/ATPase pump?
Na-K-ATPase keeps the cytoplasmic [Na] lower than tubular [Na] and maintains electrochemical gradient for passive Na transport across luminal membrane
How does glucose leave the cells into the bloodstream?
Glucose exits out at basolateral membrane via SGLT2 (sodium-glucose cotransporter) by facilitated diffusion driven by high [glucose] in the cell
What is familial renal glycosuria?
genetic defect in SGLT2 protein: just like similar defect in intestinal protein SGLT1 – glucose-galactose malabsorption
What other substances are co-transported with Na?
Cl- and aa (symport) and H+ (antiport)
What techniques can we use to investigate tubular function?
- Clearance studies ✔
- Micropuncture & Isolated Perfused Tubule
- Electrophysiological Analysis
- Potential measurement
- Patch clamping
(1 = applied to man, 2 & 3 = applied to lab animals)
Explain how micropuncture is carried out
only applied to lab animals
- Puncture
- Inject Viscous oil
- Inject fluid for study
- Sample and analyse
How is the electric potential used to determine tubular function?
Electrodes (micropipettes of very small diameter <0.5μm) inserted into cell and the Potential difference measured across whole cell epithelium
Combine with microperfusion to alter potential difference (PD)
What does the electric potential method measure?
Measure whether ion moving with/against electrochemical gradient
Actively transported?
Compare patch clamping to electric potential method
Rather than insert a microelectrode through membrane, a blunt-tip pipette (opening ~0.5-1 µm) is pressed against the cell membrane until a seal forms between electrode tip and membrane surface.
Plasma membrane can be pulled away from the cell and placed in a test solution of desired composition
Explain how patch clamping works
Current flow through individual ion channel measured
Measure electrical resistance
- Across patch of cell membrane
- Changes when channels open/close
Types of channels & response to drugs & hormones
Describe the cellular structure of tubules
Throughout its length the nephron is comprised of a single layer of epithelial cells resting on a basement membrane. There are characteristic differences in the structure of the cells which reflect their different functions.
What are the 2 types of nephron?
- Cortical nephron
- Juxtamedullary nephron
Outline the features of the Cortical nephrons
Cortical nephron
- 85%
- Don’t extend into medulla
- Short Loop of Henle (LoH)
Describe the juxtamedullary nephrons features
Juxtamedullary nephron
- 15%
- Penetrate deep into medulla
- Long Loop of Henle (LoH)
What is the major difference between the 2 types of nephron?
The major anatomic difference between the Cortical nephrons & Juxtamedullary nephrons is the length of the loops of Henle
The Vascular system is also different.
What is the role of the juxtamedullary nephrons?
Juxtamedullary nephrons have long-reach loops that penetrate deep into the medulla. These play a crucial role in concentrating and diluting urine.
Where is the Proximal Convoluted Tubule (PCT) located?
Directly adjacent to Bowman’s capsule
How is the PCT got such high capacity for reabsorption?
special cellular characteristics:
- highly metabolic, numerous mitochondria for active
transport
- extensive brush border on luminal side ⇒ large surface
area for rapid exchange
How much filtrate is reabsorbed at the PCT?
Major site of reabsorption
~65-70% of filtered load reabsorbed here
How does reabsorption occur in the PCT?
Driven by the Na/K ATPase pump as Na moves down its conc. Gradient, taking all the glucose and a.a with it back into blood
How is water reabsorbed from the PCT?
Water is also reabsorbed by osmosis
Describe the protein content in GFR
Glomerular filtrate is protein free but some small proteins (<60kD) get through
What is the fate of proteins found in the GFR?
Any small protein that may escape into the filtration system are taken up by lysosomes via endocytosis and degraded → a.a + sugars to be reabsorbed into blood
What is the consequence of Fanconi’s Syndrome?
where all PCT reabsorptive mechanisms are defective so all the solutes are present in urine rather than begin reabsorbed
What are the 3 functionally distinct segments of the loop of henle?
- thin descending
- thin ascending
- thick ascending
Describe the structure of the thin ascending limb
Thin epithelial cells, no brush border, few mitochondria & low metabolic activity
Can travel variable distance into medulla
Describe the cellular structure of the thick ascending limb
thick epithelial cells, extensive lateral intercellular folding, few microvilli, many mitochondria ⇒ high metabolic activity
Extends back into cortex
What is the role of the loop of henle?
LoH critical role in concentrating/diluting urine
» adjusting rate of water secretion/absorption
How is water reabsorbed from the descending limb?
An osmolality gradient is created in the LoH tissue in the medulla, pulling water out of LoH back into blood by osmosis
Describe the loop of Henle’s permeability to water
Only the descending limb is permeable to water
Both thin/thick ascending limb are impermeable to water but actively reabsorbs Na
Where on the loop of Henle do loop diuretics cause their effect?
Ascending limb is site of action for Loop diuretics, causing 20% of filtered Na to be excreted, by blocking Na-transport out of LoH e.g. Furosemide
Usually due to CVS pathologies
What is the medullary interstitium?
The tissue surrounding the loop of Henle in the renal medulla
What causes an osmotic gradient in the medulla?
Solutes accumulate in the renal medullary interstitium, maintained by a balanced inflow and outflow of solutes and water in the medulla
How is the medullary osmotic gradient maintained?
A high [solute] (high osmotic pressure) is generated and maintained in medullary interstitium and tubule fluid becomes hypotonic
What is counter-current flow?
Flow of fluid is in opposite directions
Describe the osmolality of the fluid present in the descending limb
Fluid entering descending limb from proximal tubule has approx. equal osmolarity to that of plasma = 300 mosm/kg
What occurs in the ascending limb?
The ascending limb is impermeable to water but has lots of NaCl transporters∴reabsorbs NaCl
Explain how the osmotic gradient is kept high in and around the LoH
as tubular fluid travels up ascending limb it becomes more dilute – solute accumulates in the interstitial fluid around the loop (in the medullary tissue space) raising it’s osmolality (increasing osmotic gradient)
What is the effect of the osmotic gradient created in the LoH?
Gradient created causes water to be drawn out by osmosis in the descending limb
What ensures the osmotic gradient between the ascending and descending limb is maintained?
Descending limb is freely permeable to water; hyperosmotic ISF causes water to leave descending limb.
→ leads to osmotic gradient between ascending and descending limb of 200 mOsm/kg.
Compare the osmolality of fluid entering and leaving LoH
Fluid that leaves the LoH is hypo-osmotic with ref to plasma (~100 mOsm/kg)
Describe the osmolality of the fluid travelling through the loop of henle
High osmolality as filtrate moves through descending limb as water is drawn out
Low osmolality as filtrate move sup through ascending limb as ions moved out
How much of the filtered Na is reabsorbed in the thick ascending LoH?
The thick ascending LoH reabsorbs approx 25% of filtered Na
- can compensate partially for any failure by PCT to reabsorb Na.
How does Na enter tunular cells?
Na enters cell via Na:K:2Cl symporter due to electrochemical difference favoring entry of Na into the cell (along with Cl and K)
How is Na transported to the peritubular capillaries from the cells?
Na is transported actively out via Na-K-ATPase, while K & Cl cross into the peritubular fluid passively creating medullary conc. Gradient
What effect do loop diuretics have on the Na:K:2Cl cotransporter?
e.g. furosemide; inhibit Na:K:2Cl cotransporter → in inhibition of net NaCl reabsorption & increased excretion of these ions along with water.
What is the vasa recta?
Capillary delivering O₂ and nutrients to cells of the loop of Henle
Explain the movement of substances through the vasa recta
VR freely permeable to solutes & H20
Descending into medulla H20 diffuses out & salts diffuse in
Reverse occurs as it ascends
How does the vasa recta help maintain an osmotic gradient with the LoH?
Blood flow in VR countercurrent to fluid flow in LoH, allowing movement of substances in and out of VR maintaining gradient
Describe the flow of blood through the vasa recta
Blood flow in VR is low ~5% of renal blood flow » minimizes solute loss from interstitium & maintains medullary interstitial gradient
Alteration of blood flow in VR can change gradient
Describe the first part of the DCT
1st part (macula densa) linked to juxtaglomerular complex Provides TGF feedback control of GFR & tubular fluid flow in the same nephron
What is the structure of the second part of the DCT?
2nd part very convoluted
What are the functions of the collecting duct?
Connects end of DCT to collecting duct – mainly in outer cortex
Overlap in functional characteristics with 2nd part of DCT
What occurs in the DCT?
Solute reabsorption continues in the absence of water reabsorption and the tubular fluid is further diluted in its passage through the distal convoluted tubule
Outline the functions of the DCT
- Solute reabsorption continues, w/out H2O reabsorption
- High Na+/K+/ATPase activity in basolateral membrane
- V. low H2O permeability
- Further dilution of tubular fluid
- ADH exert actions
- Acid-base balance via secretion of NH3
How is the collecting duct formed?
Collecting ducts formed by joining of collecting tubules
cuboidal epithelia, very few mitochondria
What are the 2 cell types in the collecting ducts?
- intercalated cells
- principal cells
What is the role of the intercalated cells in the collecting duct?
Involved in acidification of urine and acid-base balance
What do the principal cells of the collecting duct do?
Role to play in Na balance & ECF volume regulation
What factors of the collecting duct contribute to the counter-current mechanism?
- Final site for processing urine
- Made very permeable to H2O by ADH
- Also permeable to Urea
How is ADH secretion initiated?
ADH secretion triggered by changes in plasma osmolality
How is osmolarity sensed?
Osmolarity is sensed in the hypothalamus by osmoreceptors, which simulate secretion from the posterior pituitary to produce ADH - makes CD permeable to water
How does ADH produce a more concentrated volume of urine?
ADH concentrates urine by triggering the kidney tubules to reabsorb water back into bloodstream rather than excreting water into urine
What is the role of ADH?
ADH conserves body water by reducing the loss of water in urine - regulated by plasma osmolarity, or [solutes] in blood
How is ADH secretion regulated?
ADH secretion can also be regulated by volume receptors and arterial baroreceptors
Outline the mechanism of ADH at a cellular level
- AVP binds to V2-receptors
- Stimulates aquaporin-2 water channel synthesis &
promotes cAMP-dependent insertion of aquaporin 2
water channels to luminal membrane of principal cells - This allows back diffusion of water down its [ ] gradient
- Vasopressin via V2 receptors activates urea
transporters in distal nephron to facilitate urea
reabsorption and urea recycling - Enables maximization of Na reabsorption in thick
ascending limb, supporting the axial hyperosmotic
gradient drawing water from the distal nephron
What is urea?
Urea is a waste product formed in the liver during metabolic breakdown of proteins
How does urea pass through the kidneys?
Urea filters freely through glomerulus and passes down the tubule
How does urea in the collecting duct contributes to the osmotic gradient?
As water is reabsorbed from CD (e.g. in ADH presence) the urea = concentrated ∴ some urea moves out of CD into surrounding capillaries and medulla interstitium contributing to the osmotic gradient around LoH
How can urea in the kidneys allow detection of renal failure?
Increasing levels of urea in kidney is a sign of pre-renal failure because reabsorption is enhanced.
Monitored using blood urea nitrogen test (BUN). Can see that urea reabsorption would increase during dehydration.
Describe the osmotic pressure of the tubular fluid entering the CD
The tubular fluid entering the CD system is always hypo-osmotic
What does the [tubular fluid] in the CD depend upon?
concentration depends on the water permeability of the duct, which is determined by ADH action
How does ADH affect water permeability to the collecting duct?
In the presence of ADH water permeability is increased.
Water reabsorption increases the CD [urea]
ADH increases duct permeability to urea ∴ reabsorption is ↑
How is medullary hyperosmolarity maintained by the CD?
Other solutes, esp. Na+ and Cl-, continue to be reabsorbed in the CD to maintain medullary hyperosmolarity → facilitates reabsorption of water in the presence of ADH
What is the effect of ADH absence?
CD becomes impermeable to H₂O + urea
Na reabsorption continues in CD = tubular fluid becomes more dilute along the duct
Large volume of urine excreted
What are the major factors contributing to [solute] build up in renal medulla?
- Active transport of Na+, co-transport of K+ & Cl- out of
thick ascending limb→medullary interstitium - Active transport of ions from CD→medullary interstitium
- Facilitated diffusion of large amounts of urea from CD→
medullary interstitium - V. little diffusion of H₂O from ascending limbs of tubules
→ medullary interstitium
