Loop of Henle with its complex anatomy and even more complicated physiology has long remained an enigma to researchers all around the world. Here we discuss about the functional anatomy and the transport characteristics of Loop of Henle.

1. Functions of Loop of Henle
Dr. Saran A K

2.  Loop of Henle
A. Functions of LoH
1. Role in Reabsorption
a) Thin Descending Limb
b) Thin Ascending Limb
c) Thick Ascending Limb
2. Role in Concentration of Urine
3. Role in Acid Base Balance
B. Applied Aspects
 References

3. • Continuation of Pars Recta of
Proximal Tubule
• Fredrich Gustav Jacob Henle
• U shaped segment
• Functionally distinct segments
• Thin Descending Segment
• Thin Ascending Segment
• Thick Ascending Segment
• Highly specialized nephron site
• extreme heterogeneity
• anatomic configuration
Organization of Human Nephron
Fig 33.2 Berne & Levy Physiology 7th Edition

4. Cortical Nephrons (85%) JG Nephrons (15%)
• Glomeruli lies in the outer
cortex
• Glomeruli juxtamedullary
cortex / inner part of cortex
• LoH has 2 parts ( tDL, TAL ) • 3 parts ( tDL, tAL, TAL )
• Thin segment is very short
barely penetrating the inner
medulla
• Long thin limb extending
into the medullary pyramids
• Drains into the peritubular
capillaries
• Drains into peritubular
capillaries and vasa recta
• Excretion of waste products • Concentration of urine by
creating a hyper osmotic
medulla

5. Thin Descending Limb Thick Ascending Limb
• 2-14mm,30 µ in diameter • 12mm, 60µ diameter
• Flat squamous cell
• Leaky Tight Junctions
• Cuboidal cell
• Tight Tight Junctions
• Few mitochondria • Large number of mitochondria
• Poorly developed luminal and
basolateral surface
• Extensive invagination of basal
membrane
5
Cellular Ultrastructure and Primary Transport in LoH
Fig 27-8 Guyton and Hall Medical Physiology

6. A. Functions of Loop of Henle
1. Role in Reabsorption
a) Thin Descending Limb (tDL)
 Absorption of H2O
1. 15% of the filtered water is
reabsorbed
2. Thin descending limb is
permeable to water, AQP 1
3. Owing to the high osmolality of
the medullary interstitium
(because of the activity of TAL)
Changes in the % of filtered substances along nephron
Fig 38-1 Ganong’s Review of Medical Physiology 26th Edition

7. • 3/4th of H2O entering tDL of Long Looped Nephrons
is rreabsorbed here
• 1/2th of H2O entering tDL of Short Looped Nephrons
is reabsorbed here
4. Tubular Fluid Osmolality
• Osmolality increases due to reabsorption of
water
• 300 to 1200 in Long looped nephrons
x4 times
• 300 to 600 in Short looped nephrons
x2 times
Osmolality changes as filtrate flows through nephron
Fig 20-4 Silverthorne Human Physiology
Absorption of H2O : Continued

8. Long
Looped
Tubular
Fluid
Peritubular
Fluid
• Electrolyte 1120 600
• Urea 80 600
1200 1200
Short
Looped
Tubular
Fluid
Peritubular
Fluid
• Electrolyte 560 400
• Urea 40 200
600 600
• Both in long and short looped nephrons,
• the predominant solutes in the tubular fluid are Na+ and Cl-,
• but substantial fraction of the peritubular fluid is Urea.
5. Composition of Tubular and Peritubular Fluid (at the tip of LoH)
Absorption of H2O : Continued

9. The medullary interstitial gradient – Na+ Cl- and Urea contribution
Fig 35.8 Berne & Levy Physiology 7th Edition
Changes in Osmolality of Tubular Fluid in different segments
Fig 28-8 Guyton and Hall Medical Physiology 12th edition

10. b) Thin Ascending Limb (tAL)
• In long looped nephrons, tAL is seen after the hairpin.
• Though structurally similar to the tDL, the tAL has completely different transport
and permeability characteristics.
1. Permeability of TAL
• virtually impermeable to water
• highly permeable to Na+ and Cl-
• moderately permeable to urea
 Passive diffusion of Na+, Cl- (absorption) and Urea (secretion) takes
place along their concentration gradients.

11. • The number of moles of Na+ plus Cl- leaving the lumen exceeds the
number of moles of urea entering due to greater permeability of tAL
to Na+ and Cl-.
• But this urea re-cycling helps to prevent urea washout from renal
medulla, thus contributing to hyperosmotic renal medulla.
2. Osmolality of Tubular and Peritubular Fluid
• The osmolality of tubular fluid slightly falls below that of the surrounding
peritubular fluid.

12. c) Thick Ascending Limb (TAL)
1. Permeability of Thick Ascending Limb
• The permeability to water is negligible
• The urea permeability is quite low
 Actively transports ions including Na+, K+ and Cl- from lumen to
peritubular space
2. Osmolality of Tubular and Peritubular Fluid
• The tubular fluid leaving the LoH is hypotonic
• Urea concentration is considerably greater than PT Fluid
• The TF/P remains constant as the volume of the tubular fluid does not
change

13. • The Na+-K+-2Cl- Symport
• The loop of Henle is responsible for the
reabsorption of ~ 40% of filtered Na+ ,
mostly in the TAL.
• Sodium is then actively extruded across
the basal lateral surfaces by the Na+-K+
ATPase.
• The entry of Na ions in the thick
ascending limb is coupled to the entry
of K+ ion and two Cl- ions.
• NKCC2 identified by Gamba
Mechanism of sodium, chloride and potassium transport TAL
Fig 27-9 Guyton and Hall Medical Physiology

14. • Load Dependent Na+ Reabsorption
• An important characteristic of the Na+-K+-2Cl- symport is that an increased amount
of Na+ will be reabsorbed by the thick ascending limb if an
increased load of Na+ is delivered to it.
• Also seen in Proximal Convoluted Tubule
• The active reabsorption of Na+ and Cl- in TAL is inhibited by certain prostaglandins
and loop diuretics such as Frusemide.

15. • Kidney Chloride Channels and Barttin
• Chlorides leave the cells at the basolateral
membrane through ClC family of kidney
chloride channels also known as ClC-K
• ClC-Ka and ClC-Kb are expressed in the TAL.
They contain a beta subunit called as
barttin and is an essential portion for the
functioning of these channels.
• A number of genes and their products have
been identified and implicated in various salt
losing tubulopathies.
Mechanism of sodium, chloride and potassium transport TAL
Fig 27-9 Guyton and Hall Medical Physiology

16. • ROMK Channels
• Some of the K that enters the cells through the Na+-
K+-2Cl- symport leaks back across the apical
membrane into the tubular lumen via ROMK
channel (renal outer medullary K+ channel)
• These channels
• ensure K+ recycling to the lumen,
essential for salt reabsorption
• set a positive trans-epithelial voltage,
that drives paracellular reabsorption of
cations
• Additional Na+ reabsorption
• Other cations namely Ca2+ and Mg2+
Mechanism of sodium, chloride and potassium transport TAL
Fig 27-9 Guyton and Hall Medical Physiology

17. oCalcium Reabsorption
• Bulk of Ca2+ reabsorption paracellular pathway
• NKCC2 and in particular ROMK generate
the “driving force”
oMagnesium Reabsorption
• 60% of the filtered Mg2+ is reabsorbed in the TAL
• Passive paracellular transit is the main route,
and it is driven by the lumen-positive
voltage. Mechanism of sodium, chloride and potassium transport TAL
Fig 27-9 Guyton and Hall Medical Physiology

18. • The synergic activity of the main transporters and channels involved
in salt absorption (NKCC2, ROMK, the chloride channel ClC with
the Barttin subunit) and the integrity of Tight Junctions are the
prerequisite to prevent electrolytes imbalance.

19. • The osmolality of the renal medulla goes on
increasing progressively from about 300 mOsm/kg
H2O at corticomedullary junction to about 1200
mOsm/kg H2O at papilla.
• Hyperosmotic interstitial fluid of the medulla is
critically important in concentrating the urine.
• An increasing interstitial osmotic gradient is guaranteed by
• Counter Current System
• Countercurrent Multiplier System
• Countercurrent Exchanger System
2. Role in Concentration of Urine : The Medullary Gradient
Vertical Osmotic Gradient in Renal Medulla
Fig 14-24 Sherwood Human Physiology 7th Ed

20. • Countercurrent System: A system where
inflow runs parallel to, counter to, and in
close proximity to the outflow for
some distance.
• In the kidney, the structures which form the
countercurrent system are loop of Henle and
the vasa recta
• Countercurrent Multiplier System formed
by the operation of U shaped loop of
Henle and is responsible for the production of
hyperosmolality and a gradient in renal medulla
• Countercurrent Exchanger System is a
similar arrangement of the surrounding vasa recta
prevents osmotic gradient dissipation
Origin of single effect
(main driving force)
Multiplication of the
single effect

21. Counter Current Multiplier System
Origin of a Single Effect
(Horizontal Gradient)
Multiplication of the single effect
(Vertical Gradient)
• Main Driving Force.
• Produces a gradient of 200 mOsm/kg H20
• The mechanism of origin of single effect in outer medulla
is different from that of the inner medulla.
• The hyper-osmolality and medullary gradient is
generated by the multiplication of the single
effect by the countercurrent multiplier
Outer Medulla
1. Active addition of Na Cl through water
impermeable TAL
Inner Medulla
1. Passive transport of Sodium Ions from tAL
2. Active Transport of Sodium and Urea from the
CD into the medullary interstitium.
• tDL : High permeability of a water but
not to solutes
• tAL : Impermeability to water but high
permeability to NaCl
• TAL : Impermeability to water and
ability to actively absorb

22. • Reabsorbs a significant fraction (15%) of the
filtered bicarbonate
• Bicarbonate concentration increases significantly
resulting from due to water reabsorption along the
descending limb
• In the TAL, bicarbonate is reabsorbed via the
transcellular pathway
• resembles bicarbonate reabsorption in the PT
through Na+ /H+ exchanger (NHE3)
activity
• Bicarbonate exit from the cells is mediated
by the Cl−/HCO3− exchanger 2 (AE2) Transport mechanisms in TAL LoH
Fig 24.7 Berne & Levy Physiology 7th Edition
3. Role in Acid Base Balance

23. • Urine ammonia excretion derives mainly from renal ammonia genesis, rather than
glomerular filtration.
• It is produced from glutamine in the Proximal Tubule as ammonium ion (NH4
+) and is
released to the luminal fluid.
• TAL has a crucial role in ammonia reabsorption via NKCC2, at
the K+ binding site substituting for potassium.
• Basolateral exit is mediated by the Na+ /NH4
+ exchanged via
• NHE4
• Na+ - HCO3
- Co- transporter
• Cl− -dependent pathway

24. B. Applied Aspects
1. Loop Diuretics
• Furosemide, Torsemide, and Bumetanide
bind NKCC2 in a reversible fashion.
• reduction in Na+ , K+ , and Cl− absorption
• overrules that the cortico-medullar osmotic
gradient
• increases urine output
• impairs paracellular cations reabsorption.
• This property has predictable beneficial effects in
several conditions, and loop diuretics are the
main therapy in fluid retentive states and
hypercalcemic conditions.

25. • Autosomal Recessive Disorder
• caused by inactivating mutations in the gene coding for the
oNa+-K+-2Cl− symporter (NKCC2)
othe apical K+ channel (ROMK)
obasolateral Cl− channel – Classical Barrter
• Decreases NaCl reabsorption and K+ reabsorption by the TAL
• causes hypokalemia and a decrease in ECFV which activates RAAS mechanism.
• characterized by
• hypokalemia, metabolic alkalosis, hyperaldosteronism
2. Barrter Syndrome

26. • Mutations in the tight junction protein claudin -16 (CLDN16)
• reduce the permeability of paracellular pathway of Ca2+ and Mg
2+, reducing reabsorption
• Characterized by
• enhanced excretion of Ca2+ and Mg2+
• high levels of Ca++ in urine which leads to nephrolithiasis
3. Familial Hypo-magnesemic Hypercalciuria

27. References
1. Ganong. Review of Medical Physiology 22nd Edition McGraw Hill
2. Best and Taylor’s Physiological Basis of Medical Practice 12th Edition Williams &
Wilkins
3. Guyton & Hall. Textbook of Medical Physiology 11th Edition Saunders Elsevier
4. Walter F Boron. Medical Physiology 2nd Edition Saunders Elsevier
5. Berne & Levy Physiology 7th Edition Elsevier
6. Ganong. Review of Medical Physiology 26th Edition McGraw Hill