5 distinct barriers for substance to be reabsorbed?
1) Leave tubular fluid by crossing luminal membrane
2) Through cytosol of tubular cell
3) Cross basolateral membrane of tubular cell to enter interstitial fluid
4) Diffuse through interstitial fluid
5) Penetrate the capillary wall to enter plasma
Why bother to filter 180L/day and then reabsorb 99% of it?
- Foreign substances are filtered into the tubule, but NOT reabsorbed into the blood
- Filtering ions and water into the tubule make regulation simple
Majority of substances are reabsorbed where; what are they?
Proximal convoluted tubule
100% of glucose, AA’s
70% of Water, Na+, K+ Phosphate, and Ca2+
What is reabsorbed in the proximal straight tubule?
Primary vs Secondary active transport?
Primary: coupled directly to an energry source (ATP)
Secondary: coupled indirectly to an energy source (due to concentration gradient of an ion)
Primary active transporters of the kidneys?
Na-K+ ATPase, Hydrogen ATPase, Hydrogen-K+ ATPase, and Calcium ATPase
Key element of proximal tubule reabsorption; location?
Na-K+ ATPase; basolateral membrane
What is tubular load and the calculation?
Amount of any substance(s) entering the tubule/min
TL(s) = P(s) x GFR
What 2 things does the operation of Na+-K+ ATPase accomplish?
1) Lowers IC [Na+] and increases IC [K+]
2) Creates low IC [Na+] and negative charge
Describe the Transcellular vs Paracellular route
Transcellular: substances move through the luminal membrane, cytosol, and the basolateral membrane
Paracellular: substances move between the tubule cells
Why is movement through the paracellular route limited?
Contain tight junctions, which are leaky and only allow some important ions (Ca2+, Mg2+, K+ and some Na+)
How do substances move through transcellular vs paracellular (transport mechanism)?
Transcellular: Passive diffusion or Active transport
What is the single most abundant cation in filtrate; how much energy is devoted to their reabsorption; almost always via what mechanism and route?
Na+; 80%; almost always active transport and via the transcellular route
Majority of Na+ ion reabsorption occurs through what channels on what surface?
Sodium leak channels on the apical surface (luminal membrane) of the proximal tubule cell
Sodium, H2O, and other substances are reabsorbed from the interstitial fluid into the peritubular capillaries by which forces?
Hydrostatic (Pi) and colloid osmotic pressure gradients (πc)
How does the diffusion of Na+ out of the cell using Na-K+ ATPase favor the movement of more Na+ into the cell?
The Na-K+ ATPase is working to get Na+ out of cell across the basolateral membrane, creating a low intracellular [Na+] and a negative intracellular electrical potential. This negative electrical potential in the cell attracts more Na+ from the tubular lumen to diffuse into the cell so that it can then be pumped out and into the interstitium for reabsorption into the capillary.
80% of the Na+ entering the tubule cells does so in exchange for what ion, via what transporter?
Exchange for H+ (secretion) via the Na-H+-exchanger 3 (NHE3) - Countertransporter/Antiporter
What is the exchange ratio for the NHE3 antiporter?
One Na+ is reclaimed from the lumen in exchange for one H+ ion
When H+ gets exchanged for Na+ by NHE3 you now have an acidic H+ ion in the lumen of the proximal tubule, what happens?
- H+ secreted into the filtrate combines with HCO3 —> H2CO3, which is quickly converted to H2O and CO2 via carbonic anhydrase
- CO2 diffuses back into the tubule cell cytosol where it combines with H2O to form H2CO3 in the presence of carbonic anhydrase. H2CO3 then dissociates into H+ and HCO3.
Once H2CO3 has dissociated in the tubular cell cytosol to form H+ and HCO3, what occurs?
H+ recycles through the NHE3 again, while HCO3 moves into the interstitial space via the NaHCO3 cotransporter
The NHE3 transporter is important for the reabsorption of what ions?
Na+, Cl-, and HCO3
Discuss chloride reabsoprtion
More H20 than Cl- is reabsorbed in the first 1/2 of the proximal tubule, which causes the [Cl-] in tubular fluid to increase about 20% along the length of the proximal tubule. This increasing concentration provides a chemical gradient that drives Cl- movement “passively” w/o need for additional energy expenditure, along the PARACELLULAR pathway.
What is present in the cell membranes of the thin descending limb, thick ascending limb, and collecting duct that determines the movement of H2O?
Thin descending: smaller amount of tight junctions, so paracellular movement of H2O occurs freely
Thick ascending/collecting duct: abundant tight junctions prohibit water movement
What prevents the transcellular movement of water?
Specialized epithelial cells in the apical membrane (luminal membrane), which are tightly packed with lipids, repelling or blocking water movement through the lipid bilayer.
What is the large class of proteins that allow the transport of water via the transcellular route?
Where is Aquaporin I located?
Membranes of the cells lining the proximal tubule and thin descending limb
Where is Aquaporin II found?
Apical membrane of the collecting duct cells
Where is Aquaporin III and IV found?
Basolateral membrane of the collecting duct
What makes Aquaporin II unique?
Subject to control mechanisms, responding to the needs of the body for water. Regulated by ADH.
Glucose is almost completely reabsorbed from the tubules via which mechanism?
Active transport molecules called SGLT’s
What is SGLT1?
High-affinity, low capacity transport proteins, responsible for 10% of glucose reabsorption and are found in the distal part of the PCT.
*High-affinity means they are active even with low concentrations of filtrate glucose
What is SGLT2?
Low-affinity, high capacity transport proteins, responsible for 90% of reabsorption, found in the first part of PCT (S1 and S2)
*Low affinity means it requires a higher concentration to fill its binding sites
What do SGLT’s link with to help them move glucose?
Link with the movement of Na+ down its electrochemical gradient to the “uphill” reabsorption of glucose
How does glucose move into the interstitial space once inside the cell; which transporters for each part of the PCT?
- GLUT2, in the S1 segment of the PCT
- GLUT 1 in the S3 segment of the PCT
Describe the overall movement of glucose from inside PCT to the cell and then to the interstitium.
Glucose (S1, S2)–> SGLT 2 –> Cell —> GLUT2–> Interstitium
Glucose (S3)–> SGLT 1–> Cell–> GLUT1 –> Interstitium
Since glucose is freely filtered across the glomerulus what is the concentration within the tubule vs. the interstitium and blood?
What is one of the pharmacological interventions for Type 2 DM?
SGLT2 inhibition, will cause less glucose to be reabsorbed and more to be excreting, decreasing the concentrations in the blood
What is the transport maximum for glucose (Tm); plasma glucose level of; what occurs past Tm?
- SGLT1 and SGLT2 will absorb filtrate glucose until all of their receptor sites are full, this is the Tm.
- Corresponds to a plasma glucose level of about 200 mg/dL.
- At this point extra glucose will pass into the bladder and will be excreted (glycosuria)
What is permeable and impermeable in the descending loop of Henle; creates what osmolarity?
- H20 is permeable (25% reabsorbed)
- Solutes NaCl impermeable
- Fluid becomes hyper-osmolar
How does reabsoprtion work in the thick ascending limb of the loop of Henle?
- Na+ and Cl- can be reabsorbed, while H20 is impermeable.
- The filtrate becomes very dilute and hypo-osmolar by the time it gets to the distal tubule
How is the thick ascending loop able to accomplish the task of intense particle reclamation?
Has very high density of Na/K ATPase along its basolateral membrane
Function of the Na-K-2Cl co-transporter; found where?
- Found on apical membrane of thick ascending limb
- Allows one Na+, one K+, and two Cl- ions to cross the apical membrane. K+ subsequently exits the cell via an apical channel back into tubular fluid, while the Cl- exits the basolateral side of the cell via a chloride channel, and the Na+ exits via Na/K ATPase.
What is the net effect of the Na-K-2Cl co-transporter mechanism?
One positive charge and two negatively charged particles have been reabsorbed from the lumen; leading to a transepithelial positive voltage.
Importance of the transepithelial positive voltage created by the Na-K-2Cl co-transporter; movement is via what kind of reabsorption pathway?
- Drives the movement of cations, Na+, Ca2+, and Mg2+ from the lumen to the basolateral side via paracellular reabsoprtion.
- Helps regulate the serum levels of Ca2+ and Mg2+, two critical cations
How is the majority of K+ reabsorbed in the PCT?
60% is reabsorbed actively by the paracellular transport mechanism
What establishes a concentration gradient for K+ reabsorption in the paracellular space?
Active K+ uptake via Na+/K+ ATPase located in the lateral cell membrane facing the lateral intercellular spaces
K+ that enters the cell actively from lateral surface is able to exit the basolateral membrane via which 3 pathways?
1) The conductive K+ channel
2) The K+/Cl- co-transporter
3) The Na+/K+ ATPase pump
What do high K+ diets lead to in regards to K+ channels?
Insertion of apical channels and therefore higher K+ secretion
Hyperkalemia from either high K+ diet or other factors causes what?
Stimulates K+ secretion within minutes
Hypokalemia from either low K+ diet or other factors causes what?
Decreases K+ secretion
What is the major mechanism of transport for NaCl in the distal tubule?
Na+-Cl- cotransport (symporter)
What is a major site for pharmacological intervention in the distal tubule; how do they work?
The Na+-Cl- symporter can be blocked by Thiazide diuretics
They act to increase the excretion of Na+ and Cl- by inhibiting the Na+-Cl- symporter.
How do Thiazides affect Ca2+?
- Reduce the urinary excretion of Ca2+, enhancing reabsorption in the DCT.
- Are used to treat kidney stones and may be useful for treating osteoporosis
What causes the release of aldosterone from the adrenal cortex?
Angiotensin II or increased plasma K+
Which 3 parts of the kidney does aldosterone have an effect on?
1) Principal cells of the collecting ducts,
2) Distal portion of DCT
3) Thick ascending loop
What does a rise in plasma K+ cause aldosterone to do?
Stimulates the release of aldosterone, which in turn increases the tubular secretion and urinary excretion of K+. At the same time it increases the tubular reabsorption of Na+ and decreases urinary excretion of Na+
Which two pathways can cause aldosterone secretion?
1) A rise in plasma K+
2) Fall in plasma Na+ stimulates RAAS pathway
Calcium homeostasis is regulated by what 3 hormones?
3) 1a,25-dihydroxy-Vitamin D
3 major effects of PTH
1) Directly stimulates bone resorption
2) Directly stimulates recovery of calcium in the kidney
3) Stimulates the production of 1a,25-dihydroxy-Vitamin D from its precursors
What has the opposite effects of PTH in bone and kidney?
Key to calcium homeostasis is?
Amount of calcium absorbed in the gut, because there are always some losses of calcium in the feces, urine, and sweat