Lecture 7: Transport in the Proximal Tubule Flashcards
Where does proximal tubule begin?
At the urinary pole of Bowman’s capsule
Urinary pole = area at which the urinary space of Bowman’s capsule converge
What are the two parts of proximal tubule?
- PCT
- Proximal Straight tubule
In both the superficial nephron and juxtamedullary nephron, the PST will end in the outer stripe of the outer medulla
What are the histological features of PCT?
- Tall brush border
- Extensive vacuolar-lysosomal system
- basolateral membrane invaginations
- Interdigitation with neighboring cells
- extensive elongated mitochondria
Its cells are bigger than cells of PST
What are the histological features of PST?
- shorter brush border
- smaller mitochondria
- less complicated basolateral membrane structure
What is the function of the proximal tubule?
Absorbs 2/3 of glomerular ultrafiltrate
~180L/day filtered and 120L/d reabsorbed
Rate of Na reabsorption is second highest in PCT
Rate of Na reabsorption decreases when it gets to PST
Reabsorption occurs isoosmotically because water follows
What is the difference between reabsorption rates of PCT and PST?
PCT is twice as fast as PST
How do you study nephron physiology?
Take two pipettes
One end perfuses one end of tubule and the other end collects fluid (using oil)
Can measure voltage difference at two ends
What drives transepithelial membrane transport of water?
Oncotic and hydrostatic pressure gradients
What drives transepithelial membrane transport of solutes?
- active and passive transport processes
- transepithelial electrochemical gradients
- apical membrane-cell and basolateral membrane-cell electrochemical gradients
- “Solvent drag”
What is responsible for bridging the gap between cells?
- tight junction
- claudins
- Adherens junction
- E-cadherin
Cells and compounds get through
Membrane either paracellulary
Or transcellularly
What is tertiary active transport?
Na/K atpase drives secondary Transport (Na/H antiport) Increased Na to the cell due to Secondary active transport Creates an additional electric gradient That will lead to influx of Cl- through Cl/HCO3- antiport (just an example)
Where is the Na/K atpase localized on the cell of the nephron?
Always on the basolateral membrane
What is the pars recta?
The other name for proximal straight tubule
PR = pars recta = PST
What is Na/K ATPase activity of PCT vs Thick ascending limb (medullary and cortical) and DCT?
Thick ascending limb and DCT has much higher Na/ATPase activity
Everything else has lower Na/K activity compared to PCT
What segments of the nephron have the highest water permeability?
PCT
PST
Thin descending limb
Vasopressin does NOT change the permeability of these guys
What segments of nephron have low water permeability?
Thin ascending limb
Thick ascending limb
DCT
Collecting ducts (EXCEPT when you give ADH)
What is difference between leaky and tight epithelium?
Leaky = does not maintain gradients because everything passes through it (except for inulin) Tight = there is a gradient maintained because only certain things pass through it
Does proximal tubule contribute to urinary dilution or concentration?
NO
Concentration/dilution is dealt with at later segments
Proximal tubule is isotonic to plasma
Are there aquaporins in the proximal tubule?
Yes for transcellular transport
AQP1
How does water get reabsorbed in PCT?
Through Aquaporin 1 transcellularly
And interstitial hypertonicity paracellularly
What is the primary driving force for water reabsorption in prox tubule?
Osmotic gradient between fluid and lumen…LINKED TO SODIUM
Sodium gradient = water reabsorption
On the apical membrane of the PCT, you have sodium channels, Na/H antiports and Na/glucose symports that bring Na into the cell
Gradient is maintained by Na/K ATPase on basolateral membrane
How does Ca, Mg2+ and Cl- move from lumen to capillary?
Paracellulary
How is Cl- absorbed in PT?
Sodium transport transcellulary from lumen will pull Cl- along with it as well
Cl- goes through paracellulary
There appears to be no NaCl coupled cotransport!
What is the difference in NaCl absorption in PT and DT (proximal and distal)?
PT does not have NaCl cotransport (they are taken up separately)
DT does have NaCl symporters
How does glucose get absorbed from the lumen in the PCT? PST?
In the PCT, the SGLT2 is used to absorb Na and glucose at a 1:1 Na/glucose ratio
-GLUT2 transporters on basolateral membrane
In the PST, the SGLT1 is used to absorb Na and glucose at 2:1 Na/glucose ratio
-GLUT1 transporters on basolateral membrane
What are the characteristics of SGLT2?
In the PCT; absorbs bulk of glucose
High capacity
Low affinity
What are the characteristics of SGLT1?
In the PST; absorbs less glucose in comparison to PCT
Low capacity
High affinity
A mutation to SGLT2 or SGLT2 will be worse?
SGLT2 = symptomatic because does bulk Transport in the PCT SGLT1 = asymptomatic because only does Some glucose transport in PST Blocking SGLT2 is potential treatment for Diabetes
What are the two solutes that are completely reabsorbed in the Proximal Tubule?
- Glucose
2. Amino acids
What does splay mean?
A reflection of variability or heterogeneity amongst nephrons in their reabsorptive capacity
What happens when reabsorption becomes saturated?
You have increased excretion to go along with the increased filtered load
Is glucose reabsorption under hormonal regulation?
No
How is phosphate transported from the luminal membrane?
Through Na-Pi symporters
- Type IIa Na-Pi symporter; 3:1 Na:H2PO4
- Type IIc Na-Pi symporter; 2:1 Na:H2PO4
- most important transporter in humans
- mutations to Type IIc = phosphaturia and hypophosphatemic rickets
Is phosphate reabsorption under hormonal control?
Yes
What hormones decreases Pi reabsorption?
- PTH
- High intake
- FGF-23
What increases Pi reabsorption?
- Phosphate deficiency
2. Growth hormone
What is the mechanism of PTH on Pi reabsorption?
PTH leads to rapid internalization (endocytosis) of NaPi cotransporters
Thereby reducing reabsorption
What is the mechanism of FGF-23 on Pi reabsorption?
Reduces expression of NaPi cotransporters on apical membrane
What do growth hormone and phosphate depletion do the Na-Pi cotransporters?
Upregulates them
There is a transporter for what types of amino acids?
- acidic
- neutral
- basic
Some can carry more than one
Can be Na-dependent or Na-independent
What can a defect in the cysteine transporter
Lead to?
Urinary tract stones
Cystine is the most insoluble of amino acids
What happens when you have defect in uric acid transporters?
Hyperuricemia, kidney stones and gout
How does one reabsorb bicarbonate?
- proton will react with bicarb in lumen to generate H2CO3
- carbonic anhydrase in nephron lumen to cleave H2CO3 to H2O and CO2
- CO2 will diffuse into the proximal tubule cell
- CO2 + OH- from water = HCO3- (through carbonic anhydrase) and then are released to blood through Na/HCO3- symporter (1:3 ratio)
Thus one needs to secrete 1 H+ for every HCO3- it reabsorbs
What happens when bicarb is not virtually all reabsorbed?
You lose a buffer
Therefore you get proximal renal tubular acidosis, pRTA, or acidication of ECF (metabolic acidosis)
80% of bicarb is normally reabsorb
What inhibits bicarb reabsorption?
PTH
What stimulates bicarb reabsorption?
Angio II
Catecholamines
How does Ca get reabsorbed by PT?
50-60% of filtered Ca load is reabsorbed in PT
Claudin-2 facilitates Ca2+ transport
Reabsorbed passively via paracellular means
What are the characteristics of Mg reabsorption in PT?
Only 5-15% gets reabsorbed
Not mediated by claudin 2 or other proteins
Only ion which is not primarily absorbed in PCT
What is solvent drag?
When water goes through paracellularly, it might drag along solutes such as K+
What is the significance of megalin and cubilin?
Cooperating receptors that are part of a complex found on proximal tubule
Used to reabsorb all the shit that are NOT electrolytes
Examples of things they reabsorb:
i. albumin
ii. myoglobin
iii. Amylase
iv. insulin
v. Aminoglycosides
If it sounds random, it is probably reabsorbed by the Megalin Cubulin complex
What are the characteristics of the Megalin-Cubulin Complex?
Composed of
i. Megalin
ii. Cubulin
iii. Amnionless
Takes up random ligands (such as albumin) and brings it into the lysosome
Lysosome digests the ligand and recycles the digested components into the bloodstream
How can the function of the Megalin-Cubulin Complex harm an individual?
Drugs are taken up by the Megalin-Cubulin Complex
Some drugs, if lysed, release toxic components, thus causing harm to the cells of the proximal tubule
What are the key characteristics of proximal tubule ammoniagenesis?
Glutamine is taken up in the cell and is converted into glutamate and then into alpha-ketoglutarate, making NH4+ with each step. Then alpha-keto glutarate is broken down into two moles of HCO3-
So 1 mol Glutamine 2NH4+ and 2HCO3-
This process is stimulated by acidosis in proximal tubule cell
Excretion of NH4+ = net gain of HCO3-
No excretion of NH4+ = formation of urea = consumption of 2 HCO3- = no HCO3- net gain
What is the significance of urea?
An end product of catabolism
Synthesized primarily in liver via urea cycle
Functions to detoxify ammonia
Urea is freely filtered
Transcellular transporters of urea in PT (which reabsorbs urea) have not yet been found like they have in other parts of the nephron (although conceivably they are there)
What happens to creatinine levels in the proximal tubule?
Creatinine can be secreted into the PT lumen via organic cation transporters
These cation transporters can be inhibited by Trimethroprima and cimitedine, which blocks creatinine secretion and increases accuracy of creatinine clearance in determining GFR
What are the two types of diuretics that affect PT function?
- Osmotic diuretics
2. Carbonic anhydrase inhibitors
What are the characteristics of osmotic diuretics in the proximal tubule?
Diuretics that increases osmolality of luminal contents
Example: mannitol
Increased luminal contents = more water gets secreted
Thus prevents reabsorption
What are the characteristics of carbonic anhydrase inhibitors on proximal tubule?
Aka acetazolamide
Inhibits carbonic anyhydrase, thereby inhibiting HCO3- breakdown in the lumen
Therefore cell cannot absorb the CO2 and H2O that is usually its byproduct
More solute in the lumen = more water secretion from PT
What is Fanconi Syndrome?
Generalized dysfunction of the proximal tubule
Variable degrees of Proximal tubule levels of Pi, glucose, amino acid and HCO3- wasiting
Leads to rickets and impaired growth in children
Leads to osteomalacia and osteoporosis in adults
What is the pathophysiology of Fanconi syndrome?
Impaired function of PT due to accumulation of intracellulary (lysosomal) amino acids, organelle dysfunction, disruption of PT endosomal structure, drug toxicity, immunologic injury affecting Na?K ATPase
What does Fanconi Syndrome lead to in kids?
- Rickets
2. impaired growth
What does Fanconi syndrome lead to in adults?
Sodium bicarbonate
Phosphate supplements
What abnormality best describes the clinical findings of this boy: Failure to thrive Low K, HCO3-, Pi, uric acid Normal sodium and glucose pH = 5.2 for urine Has glucose in the urine Aminoaciduria?
Defect in proximal tubule Na/K ATPase function (because of the broad range of deficiencies)
Kid has Fanconi’s Syndrome
What is the treatment for Fanconi Syndrome?
Sodium bicarbonate
Phosphate supplements
