I. The proximal tubule reabsorbs sodium, bicarbonate, glucose and other solutes. Carbonic anhydrase and NHE3 transporters facilitate reabsorption. Carbonic anhydrase inhibitors and adenosine receptor antagonists act in the proximal tubule. II. In the loop of Henle, the thin descending limb is water permeable while the thick ascending limb actively transports sodium via NKCC2 transporters. Loop diuretics block NKCC2. III. The distal convoluted tubule reabsorbs sodium and chloride via NCC transporters. Thiazide diuretics block NCC. IV. The collecting duct regulates sodium, potassium and water balance.

1. Domina Petric, MD

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 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
Very high Acid (uric acid)
and base
transporters
None
Thin
descending
limb of
Henle´s loop
Passive reabsorption of
water
High Aquaporins None

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
Very low 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
Variable Aquaporins Vasopressin
antagonists

4. I.

5.  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.
Proximal tubule

6.  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.
Proximal tubule

7. 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.
Proximal tubule

8. 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.
Proximal tubule

9.  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.
Proximal tubule

10.  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.
Proximal tubule

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

12.  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.
Proximal tubule

13. 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.
Proximal tubule

14.  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.
Proximal tubule

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

16.  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.
Proximal tubule

17.  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.
Proximal tubule

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

19. II.

20.  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.
Loop of Henle

21. 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.
Loop of Henle

22. 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.
Loop of Henle

23.  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.
Loop of Henle

24.  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.
Loop of Henle

25. III.

26.  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).
Distal convoluted tubule

27.  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.
Distal convoluted tubule

28. IV.

29.  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.
Collecting tubule system

30.  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.
Collecting tubule system

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

32.  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.
Collecting tubule system

33.  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 10-50 mV lumen-negative electrical
potential develops.
Collecting tubule system

34.  Sodium that enters the principal cell from the
tubular fluid is then transported back to the blood
via the basolateral Na+/K+-ATPase.
 The 10-50 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+.
Collecting tubule system

35.  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.
Collecting tubule system

36.  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.
Collecting tubule system

37.  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.
Collecting tubule system

38.  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.
Collecting tubule system

39. 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.
Collecting tubule system

40.  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.
Collecting tubule system

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