Gene Models And Nephron Function Flashcards
Main function of nephron
- Tubular reabsorption
- Movement of ions, water and small molecules into capillaries
- Each kidney has ~1-1.5 million nephron (therefore 1-1.5 million glomeruli)
Glomerular filtration of plasma
- ~20% plasma removed
- 180L/day filtrate
- Plasma vol =2.75L
- Max urine vol. excretion=23L
- Plasma filtered 65 times/day
What is permitted/ restricted in filtration by glomerular?
- Permitted:
- H2O
- Small molecules
- Restricted:
- Blood cells
- Proteins
Ultrafiltrate - the plasma processed by renal tubule - has passed through semipermeable membrane with v. small pores (ie through glomerular)
- Conc of ions in plasma same as in Bowman’s capsule
- Consists of protein free plasma
- 1% protein filtered (albumin) (small proteins)
- Large proteins in urine=glomerula breakdown
- Small proteins in urine=from proximal tubule
What are the pathways of tubular transport?
- Transcellular pathways = across the cell
- Reabsorption: ions, water, solutes
- Secretion ( from blood into lumen of tubule)
- Paracellular secretion/ absorption
- between cells - tight junctions mediate
Reabsorption in the proximal tubule
- Bulk reabsorbing epithelium
- High apical SA
- Lots of mitochondria (ATP) - energy needed
- Bulk reabsorption: 70% filtrate reabsorbed (70% of Na, 70% of 180L water reabsorbed)
- ~100% of glucose and amino acids reabsorbed
- 90% bicarbonate (HCO3-) reabsorbed (regulation of pH and body fluids)
Movement across proximal tubule (basolateral cell membrane proteins)
- Na/K ATPase - ubiquitous transport protein (found everywhere)
- hydrolyses ATP to drive influx of 3Na out and 2K in - against electrochemical grdt
- primary active transport protein
- maintaining low intracellular Na conc
- K channel
- sets -ve membrane potential
- driving force of Na influx (mediated by proteins)
Movement across membranes of proximal tubule cells (apical membrane)
- Na/ Glucose transport molecule: SGLT1&2
- Facilitated diffusion (Na coupled transport)
- Net reabsorption of glucose
- Secondary active transport
- Phosphate reabsorption: NaPi11
- Na/AA
- Net reabsorption of both (100% AA reabs)
Movement across membranes of proximal tubule cells (Paracellular Movement)
- Water follows (Na) isosmotically
- Conc ~ same between start and end of proximal tubule
Proximal tubule: NaPi11 KO mice phenotype
- Young animals struggle to maintain phosphate
- Early abnormal skeletal development
- Older mice show compensation
- Not too much difference in skeleton in older mice
Proximal tubule: SGLT1&2
- 14 transmembrane spanning domains
- extra and intercellular projections
- binding sites for Na and glucose - flips over and releases them into cell
- Slightly different sequence between 1 and 2
- 1 monmer - fully functional protein
What are the symptoms and cause of Familial Renal Glycosuria?
- Inherited mutation in SGLT2
- Increased urinary glucose (can’t reabsorb as much glucose) : few to a 100g/day
- Normal plasma glucose
- No obvious kidney damage
- No general tubule damge
- Carriers - heterozygous - mild symptoms
- Autosomal recessive - severe symptoms
Bicarbonate handling (reabsorption) in the proximal tubule (apical membrane)
- Maintaining body fluid pH
- NHE3: Na/H+ exchange protein
- Na in H out (H+HCO3-=H2CO3)
- Carbonic anhydrase (H2CO3) on outer surface of apical membrane
- CO2 freely diffusible
- H2O - water channels (aqua porin 1)
- Combine to form H2CO3 in cell
Bicarbonate handling (reabsorption) in the proximal tubule (basolateral membrane)
- Na/HCO3- transport protein
- high conc of HCO3
- drives reabsorption of Na and HCO3
- High water permeability
Proximal tubule: NHE3 KO mice
- KO incapable of making NHE3
- Lose ability to reabs HCO3 - plasma HCO3 levels drop
- HCO3 is an important buffer (esp in plasma)
- Increased H ( because of HCO3 decrease) = decreased pH - particaluarly effects excitable cells)
- Decreased systolic BP as less fluid reabsorption - increased urine flow rate
- (decreased EC fluid vol=decreased BP
Proximal tubule: effects of NHE3 KO
- Inhibit H secretion
- Inhibits Na and HCO3 transport
- Decreased fluid reabsorption
- Decreased plasma HCO3
- Decreased pH
- Decreased ECFV
- Decreased BP
Secretion by the proximal tubule
- Removal of plasma protein bound substances
- Removal of foreign compounds
- eg penicillin (plasma levels weren’t reaching therapeutic levels - lots of it was secreted into urine)
Function of the Loop of Henle (LoH)
- Fluid is essentially the same throughout loop
- Concentration of urine
- Reabsorption of Na, Cl, H2O, Ca, Mg
- Site of action of loop diuretics
LoH: Loop structure
Thin and thick ascending limbs are water impermeable.
Movement across membranes of Thick Ascending Limb (TAL)
Apical membrane
- NKCC2: Na/Cl/K co-transport protein
- must bind 1:2:1 to move into cell
- ROMK (Kir1.1): K channel
Basolateral membrane
- CLCK and Barttin (beta/accessory subunit) work together for normal function
- Net reabs of Cl
Paracellular reabsorption
- Na and Cl reabsorption drives reabs of Ca and Mg
TAL: Causes of Bartter’s Sydrome
- Recessive inheritance
- Loss of function mutations in:
- NKCC2 or
- ROMK (isn’t enough K in plasma so NKCC2 and therefore CLCK can’t work) or
- CLCK/ Barrtin (Cl can’t leave so increased Cl conc so NKCC2 can’t bring in Cl - grdt works against it)
TAL: Barrter’s sydrome symptoms
- Salt wasting (loss of Na and Cl in urine)
- Polyuria (increase in urine flow rate) (reduced H2O reabs b/c loss of Na and Cl in urine)
- Hypotension
- Hypokalaemia (low plama K)
- Metabolic alkalosis (high pH)
- Hypercalciuria (Ca in urine) - increased risk of:
- Nephrocalcinosis - stone formation
LoH: Loop Diuretics
- Furosemide (Frusemide) and Bumetanide block NKCC2
- Treatment of high BP
- Particularly in pts where high BP is due to high ECFV eg oedema
- Side effects:
- Bartter’s-like symptoms
Function of Early Distal Tubule (DT)
- Reabsorption of Mg, Na, Cl
- dilute fluid
- Sensitive to thiazide diuretics
Movement across membranes Early DT
Apical membrane
- NCC: Na/Cl transport
- (driven by Na/K ATPase & K channel)
- Mg channel
- eflux pathway not currently known
- Mg reabs
Basolateral membrane
- Na/K ATPase
- CLCK & Barttin: Cl reabs
Paracellular reabs
- Water ( driven by net reabs of Na and Cl)
Early DT: Cause of Gitelman’s Syndrome
- Loss of function mutation in NCC
- Recessive inheritance
Early DT: Gitelman’s Syndrome symptoms
- Early DT rather than TAL => not Bartter’s but similar symptoms
- Salt wasting
- Polyuria
- Hypotension
- Hypokalaemia
- Metabolic alkalosis
- Hypocalciuria - low Ca in urine => unclear why but suggests loss of Na and Cl reabs (Bartters - high Ca)
Early DT: Thiazide Diuretics
- Chlorothiazide - blocks NCC
- Treatment for high BP
- Side effects: Gitelman’s-like symptoms
What does being heterozygous for a mutation in ROMK, NCC, or NKCC2 protect against?
- Hypertension
- Mean BP lower than normal
- Less likely to have problems associated with hypertension
Function of the Late Distal, Connecting Tubules and Cortical Collecting Duct (CCD)
- Conc. of the urine
- Reabs of Na and H2O
- Secretion of K and H
Cell Types Of The Late DT and CCD
- Principal
- Main site for Na and H2O reabs
- K and H secretion
- Intercalated
- alpha-IC (a-IC) and beta-IC (B-IC)
- Depending on acid-base status of body - causes change
- a-IC <=> B-IC
- H secretion and reabs
- HCO3 reabs and secretion
Movement across Principal Cell (apical) membrane
- Low intracellular Na conc
- ENaC: epithelial Na channel
- down electrochemical grdt
- regulated
- ROMK: K secreted
- determines urine K content depending on plasma K
- Aquaporin 2
- up/down regulated to change urine flow rate
Movement across Principal Cell (basolateral) membrane
- Kir 2.3
- recycling K
- Aquaporin 3&4
Diseases associated with the principal cell
- Diabetes insipidus (AQP2)
- Liddle’s syndrome (ENaC)
- Pseudohypoaldosteronism
Principal cell diuretic
- Amiloride
- Blocks ENaC
- Treatment: high BP
- K sparing diuretic
Movement across a-IC membrane
- H secretion and HCO3 reabs (HCO3 created by cell - not filtered HCO3)
Apical
- Proton pump pumps H into urine
Basolateral
- AE1: HCO3/Cl pump
- Cl channel - recycling Cl
Typically in excess acid - more a-IC than B-IC
DT Acidosis cause
- Genetic inheritance
- Mutation in AE1
- Mutant protein is mistargeted
- Trafficking defect - protein trafficks to apical membrane
- HCO3 is not reabs - it’s secreted
- Struggle to retain sufficient HCO3
DT Acidosis symptoms
- Nephrocalcinosis (srone formation)
- Metabolic acidosis (low pH)
Movement across B-IC membrane
- H and Cl reabsorbs and HCO3 secretion
Apical
- AE1: HCO3/ Cl pump
Basolateral
- Proton pump - reabs H
- Cl channel
pH too high - alkylosis
Medullary CD
- Low Na permeability
- High H2O and urea permeability in presence of vasopressin
- Kidney- use urea to allow us to produce conc urine
Kidney: Na reabs summary
- PT 70%
- LoH 20%
- DT & CCD 9% (ENaC -aldosterone regulates ENaC)
- Total = 99%
- Most of filtered Na reabs
Kidney: H2O reabs summary
- PT 70%
- LoH 5%
- DT & CCD 24% (regulated by vasopressin)
- Total = 99%
- Most of filtered water reabs
Kidney: K reabs summary
- PT 80%
- LoH 20%
- DT & CCD (K secreted in urine)
Kidney: H reabs & secretion summary
- Secretion:
- PT
- Principal cell
- a-IC
- Reabs:
- B-IC
Kidney: HCO3 reabs & secretion summary
- Secretion
- B-IC
- Reabs
- PT
- Principal cell
- a-IC
Acute Renal Failure
- Causes: pre-renal/renal/ post renal (urinary blockage)
- Fall in glomerular filtration rate over hrs/days
- Impaired fluid & electrolyte homeostasis
- Lasts ~1week (reversible)
- Accumulation of nitrogenous waste
- Treatment: dialysis
Acute Renal Failure symptoms
- Hypervolaemia (expansion of ECFV)
- Oliguria (reduced urine vol) due to low GFR
- causes hypertension
- Hyperkalaemia - lack of K secretion
- cardiac excitabilty - increased risk of arrhythmia
- Acidosis - depression of CNS
- High urea/ creatine
- impaired mental function
- nausea
- vomiting
