1. Renal tubule transport mechanisms
Domina Petric, MD
Renal tubule transport mechanisms

2. Segment
Functions
Water permeability
Primary transporters and drug targets at apical membrane
Diuretic with major action
Glomerulus
Formation of glomerular filtrate
Extremely high
None
Proximal convoluted tubule (PCT)
Reabsorption of 65% of filtered Na+,K+, Ca2+ and Mg2+ ; 85% of NaHCO3 and nearly 100% of glucose and amino acids. Isoosmotic reabsorption of water.
Very high
Na/H (NHE3), carbonic anhydrase
Carbonic anhydrase inhibitors, adenosine antagonists
Proximal tubule, straight segments
Secretion and reabsorption of organic acids and bases, including uric acid and most diuretics
Acid (uric acid) and base transporters
Thin descending limb of Henle´s loop
Passive reabsorption of water
High
Aquaporins

3. Segment
Functions
Water permeability
Primary transporters and drug targets at apical membrane
Diuretic with major action
Thick ascending limb of Henle´s loop
Active reabsorption of 15-25% of filtered Na+, K+, Cl-; secondary reabsorption of Ca2+ and Mg2+
Very low
Na/K/2Cl (NKCC2)
Loop diuretics
Distal convoluted tubule (DCT)
Active reabsorption of 4-8% of filtered Na+ and Cl-; Ca2+ reabsorption under parathyroid hormone control
Na/Cl (NCC)
Thiazides
Cortical collecting tubule (CCT)
Na+ reabsorption (2-5%) coupled to K+ and H+ secretion
Variable
Na channels (ENaC), K channels, H+ transporter, aquaporins
K+-sparing diuretics, adenosine antagonists
Medullary collecting duct
Water reabsorption under vasopressin control
Aquaporins
Vasopressin antagonists

4. I.
Proximal tubule

5. Proximal tubule
Sodium bicarbonate (NaHCO3), sodium chloride (NaCl), glucose, amino acids and other organic solutes are reabsorbed via specific transport system in the early proximal tubule (proximal convoluted tubule, PCT).
Potassium ions (K+) are reabsorbed via the paracellular pathway.
Water is reabsorbed passively, maintaing the osmolality of proximal tubular fluid at nearly constant level.

6. Proximal tubule
As tubule fluid is processed along the length of the proximal tubule, the luminal concentrations of these solutes decrease relative to the concentration of inulin.
Inulin is an experimental marker filtered, but neither secreted nor absorbed by renal tubules.
In the proximal tubule is absorbed 66% of filtered sodium ions, 85% of the NaHCO3, 65% of potassium ions, 60% of water and all of the filtered glucose and amino acids.

7. Proximal tubule They induce NaCl diuresis.
Only one group of diuretics (carbonic anhydrase inhibitors) acts predominantly in the PCT.
A drug that would specifically block proximal tubular absorption of NaCl, could be a powerful diuretic.
Adenosine receptor antagonists act mainly in the PCT.
They induce NaCl diuresis.

8. Proximal tubule
Sodium bicarbonate reabsorption by the PCT is initiated by the action of a Na+/H+ exchanger (NHE3) located in the luminal membrane of the proximal tubule epithelial cell.
This transport system allows Na+ to enter the cell from the tubular lumen in exchange for a proton (H+) from inside the cell.

9. Proximal tubule
Na+/K+-ATPase is present in all portions of the nephron.
It is located in the basolateral membrane and pumps the reabsorbed Na+ into the interstitium so as to maintain a low intracellular Na+ concentration.
The H+ secreted into the lumen combines with bicarbonate (HCO3-) to form H2CO3 (carbonic acid).
Carbonic acid is rapidly dehydrated to CO2 and H20 by carbonic anhydrase.

10. Proximal tubule
Carbon dioxide produced by dehydration of carbonic acid enters the proximal tubule cell by simple diffusion.
There is then rehydrated back to carbonic acid, also facilitated by intracelular carbonic anhydrase.
After dissociation of carbonic acid, the H+ is available for transport by the Na+/H+ exchanger.
HCO3- is transported out of the cell by a basolateral membrane transporter.

11. Proximal tubule
Bicarbonate reabsorption by the proximal tubule is dependent on carbonic anhydrase activity.
Carbonic anhydrase can be inhibited by acetazolamide and other carbonic anhydrase inhibitors.

12. Proximal tubule
Adenosine is released as a result of hypoxia and ATP consumption.
It is a molecule with four different receptors and complex effects on Na+ transport in several segments of the nephron.
Adenosine reduces glomerular filtration rate (GFR) to decrease energy consumption by the kidney, but increases at the same time proximal reabsorption of Na+ via stimulation of NHE3 activity.

13. Proximal tubule
Adenosine A1-receptor antagonists significantly blunt both proximal tubule NHE3 activity and collecting duct NaCl reabsorption.
These antagonists have potent vasomotor effects in the renal microvasculature.

14. Proximal tubule
HCO3- and organic solutes are largely removed from the tubular fluid in the late proximal tubule.
The residual luminal fluid contains predominantly NaCl.
Na+ reabsorption continues.
H+ secreted by the Na+/H+ exchanger can no longer bind to HCO3-.
Free H+ causes luminal pH to fall, activating Cl-/base exchanger.

15. The net effect of parallel Na+/H+ exchange and
Proximal tubule
The net effect of parallel Na+/H+ exchange and
Cl-/base exchange is NaCl reabsorption.

16. Proximal tubule
Water is reabsorbed in the PCT in response to osmotic forces.
Luminal fluid osmolality remains nearly constant along its length.
If large amounts of an impermeant solute (osmotic diuretic mannitol) are present in the tubular fluid, water reabsorption causes the concentration of the solute to rise.
As salt concentrations become diminished further, water reabsorption is prevented.

17. Proximal tubule
Organic acid secretory systems are located in the middle third of the straight part of the proximal tubule: S2 segment.
These systems secrete a variety of organic acids into the luminal fluid from the blood: uric acid, NSAIDs, diuretics, antibiotics.
These systems help deliver diuretics to the luminal side of the tubule.

18. Proximal tubule
Organic base secretory systems (creatinine, choline) are present in the early (S1) and middle (S2) segments of the proximal tubule.

19. II.
Loop of Henle

20. Loop of Henle
The proximal tubule empties into the thin descending limb of Henle´s loop at the boundary between the inner and outer stripes of the outer medulla.
Water is extracted from the descending limb of this loop by osmotic forces found in the hypertonic medullary interstitium.
Impermeant luminal solutes (mannitol) oppose this water extraction and have aquaretic activity.

21. Loop of Henle TAL is nearly impermeable to water.
The thin ascending limb is relatively water-impermeable, but is permeable to some solutes.
The thick ascending limb (TAL) follows the thin limb of Henle´s loop.
TAL actively reabsorbs NaCl from the lumen: about 25% of the filtered sodium.
TAL is nearly impermeable to water.

22. Loop of Henle
Salt reabsorption in the TAL dilutes the tubular fluid: diluting segment.
Medullary portions of the TAL contribute to medullary hypertonicity and also play an important role in concentration of urine by the collecting duct.

23. Loop of Henle
The NaCl transport system in the luminal membrane of the TAL is a Na+/K+/2Cl- cotransporter (NKCC2).
This transporter is selectively blocked by LOOP DIURETICS.
NKCC2 is itself electrically neutral, but the action of the transporter contributes to excess K+ accumulation within the cell.

24. Loop of Henle
Back diffusion of K+ into the tubular lumen causes a lumen-positive electrical potential.
This potential provides the driving force for reabsorption of cations, including magnesium and calcium, via the paracellular pathway.
Inhibition of salt transport in the TAL by loop diuretics reduces the lumen-positive potential and causes an increase in urinary excretion of divalent cations in addition to NaCl.

25. Distal convoluted tubule
III.
Distal convoluted tubule

26. Distal convoluted tubule
Only about 10% of the filtered NaCl is reabsorbed in the distal convoluted tubule (DCT).
This segment is relatively impermeable to water.
NaCl reabsorption further dilutes the tubular fluid.
The mechanism of NaCl transport in the DCT is an electrically neutral thiazide-sensitive Na+ and Cl- cotransporter (NCC).

27. Distal convoluted tubule
K+ does not recycle across the apical membrane of the DCT.
There is no lumen-positive potential in this segment.
Ca2+ and Mg2+ are not driven out of the tubular lumen by electrical forces.
Ca2+ is actively reabsorbed by the DCT epithelial cell via an apical Ca2+ channel and basolateral Na+/Ca2+ exchanger.
This process is regulated by parathyroid hormone.

28. Collecting tubule system
IV.
Collecting tubule system

29. Collecting tubule system
The collecting tubule system (CTS) connects the DCT to the renal pelvis and the ureter.
Consists of:
connecting tubule
collecting tubule
collecting duct
The collecting duct is formed by the connection of two or more collecting tubules.

30. Collecting tubule system
CTS is responsible for only 2-5% of NaCl reabsorption by the kidney, but still it plays an important role in renal physiology and diuretic action.
CTS is responsible for tight regulation of body fluid volume and for determining the final Na+ concentration of the urine.
It is the site at which mineralocorticoids exert a significant influence.

31. Collecting tubule system
CTS is the most important site of K+ secretion by the kidney and site where all diuretic-induced changes in K+ balance occur.

32. Collecting tubule system
The PRINCIPAL CELLS are the major sites of Na+, K+ and water transport.
The INTERCALATED CELLS (α, β) are the primary sites of H+ (α cells) or bicarbonate (β cells) secretion.
The α and β intercalated cells are very similar, except that the membrane locations of the H+-ATPase and Cl/HCO3- exchanger are reversed.
Principal cells do not contain apical cotransport systems for Na+ and other ions.

33. Collecting tubule system
Principal cell membranes exhibit separate ion channels for Na+ and K+.
These channels exclude anions.
Transport of Na+ and K+ leads to a net movement of charge across the membrane.
Na+ entry into the principal cell predominates over K+ secretion into the lumen.
That is why mV lumen-negative electrical potential develops.

34. Collecting tubule system
Sodium that enters the principal cell from the tubular fluid is then transported back to the blood via the basolateral Na+/K+-ATPase.
The mV lumen-negative electrical potential drives the transport of Cl- back to the blood via the paracellular pathway and draws K+ out of cells through the apical membrane K+ channel.
Important relationship: between Na+ delivery to the CTS and the resulting secretion of K+.

35. Collecting tubule system
Upstream diuretics increase sodium delivery to this site and enhance potassium secretion.
If sodium is delivered to CTS with an anion, that can not be reabsorbed as readily as chloride, the lumen-negative potential is increased.
Potassium secretion is then enhanced.
This mechanism and enhanced aldosteron secretion due to volume depletion are the basis for most diuretic-induced potassium wasting.

36. Collecting tubule system
Reabsorption of sodium via the epithelial Na channel (ENaC) and its coupled secretion of potassium is regulated by ALDOSTERONE.
Aldosterone is steroid hormone that increases the activity of both apical membrane channels and the basolateral Na+/K+-ATPase.
This leads to an increase in the transepithelial electrical potential and a dramatic increase in both sodium reabsorption and potassium secretion.

37. Collecting tubule system
CTS is also the site at which the final urine concentration is determined.
Principal cells also contain a regulated system of water channels.
Antidiuretic hormone (ADH, vasopressin, AVP) controls the permeability of these cells to water by regulating the insertion of pre-formed water channels (aquaporin-2, AQP2) into the apical membrane.

38. Collecting tubule system
Vasopressin receptors in the vasculature and central nervous system (CNS) are V1 receptors.
Those in the kidney are V2 receptors.
V2 receptors act via a G protein-coupled, cAMP-mediated process.
In the absence of ADH, the collecting tubule (and duct) is impermeable to water.
Dilute urine is produced.

39. Collecting tubule system
ADH markedly increases water permeability.
This leads to the formation of a more concentrated final urine.
ADH also stimulates the insertion of urea transporter UT1 molecules into the apical membranes of collecting duct cells in the medulla.

40. Collecting tubule system
Urea concentration in the medulla plays an important role maintaining the high osmolarity of the medulla and in the concentration of urine.
ADH secretion is regulated by serum osmolality and by volume status.
ADH antagonists are called VAPTANS.

41. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.