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Functions of Loop of Henle
The document details the functions of the Loop of Henle, highlighting its role in reabsorption of water, concentration of urine, and acid-base balance. It describes the distinct characteristics and functions of the thin descending limb, thin ascending limb, and thick ascending limb, including ion transport mechanisms and their contributions to the renal medulla's osmotic gradient. Additionally, it discusses applied aspects such as the effects of loop diuretics and genetic disorders like Bartter syndrome.
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Functions of Loop of Henle
- 1. Functions of Loopof Henle Dr. Saran A K
- 2. Loop ofHenle 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 ofPars 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 LimbThick 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 ofLoop 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 ofH2O 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 1120600 • 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 interstitialgradient – 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 AscendingLimb (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 numberof 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 AscendingLimb (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 DependentNa+ 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 ChlorideChannels 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 • Bulkof 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 synergicactivity 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 osmolalityof 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 MultiplierSystem 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 asignificant 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 ammoniaexcretion 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 RecessiveDisorder • 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 inthe 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. Reviewof 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
Editor's Notes
- #4 Loop of Henle, as you know is the continuation of the terminal part of the proximal tubule known as the pars recta. It was named after the German anatomist Fredrich Gustav Jacob Henle It is a U shaped segment with two limbs divided into functionally distinct segments namely the thin descending limb and thin and thick ascending limb. The descending limb is thin throughout in all the nephrons. The ascending limb has thin and thick portions in a typical juxtamedullary nephron. This part of the renal tubule is a highly specialized site because of its extreme heterogeneity among the different component parts (in terms of histology ) and its special anatomical configuration.
- #5 Before going to the rest of the details, we will now see the two types of nephron that we see in the human kidney. First one is the cortical nephron which comprises of almost 85% of the total nephrons. These nephrons are placed higher up in the cortex and their glomeruli lies in the outer cortex and their LoH has two parts, the thin descending limb and the thick ascending limb. Here the thin descending limbis short and barely penetrates the inner medulla. On the other hand the JG nephrons which is 15% of the total has their glomeruli more deep in the inner part of the cortex/ juxta- medullary cortex. They have an additional part in their LoH known as the thin ascending limb and their long thin limb extends upto the renal pyramids. The vascular structures supplying the nephrons also differ. The cortical nephrons are drained by the peritubular capillaries alone while the JG Nephrons are drained by both peritubular capillaries and vasa recta. Functionally, the cortical nephrons are for the excretion of waste products and although they are less in number, the JG Nephrons play a significant role in creating an hyper osmotic medulla inturn facilitating the concentration of urine.
- #6 Now, coming to the parts of the LoH, we broadly divide it under two headings. The thin descending limb and the Thick ascending Limb. The thin descending limb varies in length between 2-14mm while the thick ascending limb measures 12mm The lining epithelium is flat squamous cell with leaky tight junctions in TDL while cuboidal cells line with tight tight junctions in the walls of TAL. This makes the thin descending limb permeable to water and thick ascending limb virtually impermeable. The increased number of mitochondria and the extensive invaginations in the basal membrane can be used to explain the various active processes in the TAL These histological features can be directly correlated with their absorptive functions and with the key role these cells play in making the medullary interstitium hyperosmotic.
- #7 We now move to the topic proper, the functions of Loop of Henle. We will first see the absorptive functions of the first part, the descending limb. Thin Descending Limb is the major site of absorption of water in the Loop of Henle amounting to 15% of the total water absorption. This is made possible by specialized channels AQP 1 aided by the high osmolality of medullary interstitium because of activity of thick ascending Limb. As you can see here, the major portion of the water reabsorption occurs in the PCT followed by the LoH
- #8 Almost 3/4 of the water entering the tDL of Long Looped and 1/2th entering Short Looped Nephron is absorbed here. This pumps up the osmolality of the tubular fluid 4 times in case of Long Looped and 2 times in case of Short Looped Hence, the increase in osmolality of tubular fluid can be attributed entirely to water absorption.
- #9 Coming to the composition of the tubular fluid and the peritubular fluid As you know, along the descending Thin Limb , the osmolality of the surrounding medium increases. At any given point along the course of the thin descending limb the osmolality of the tubular and the peritubular fluid is the same, thanks to the freely permeable nature of the thin descending limb. But if we see the cause for this osmolality in both cases we can see the predominant solutes contributing to the high osmolality in the tubular fluid is Na and Cl, while in the peri-tubular fluid it is Urea.
- #10 Now, if we compare the long and the short looped nephrons, was we move from the cortex to the medulla, this contribution of urea towards the medullary interstitial gradient also increases. The second figure shows the changes in the osmolality of the tubular fluid as it passes through the different segments and it clearly shows an increase in the osmolality towards the middle region denoting the tip of the Loop of Henle.
- #11 Now, we will see the absorptive functions of the thin ascending limb. As mentioned earlier, it is only seen in the long looped nephrons. Through the tAL is structurally similar to the tDL, it has completely different transport and permeability characteristics in a way that It is virtually impermeable to water And highly permeable to Na and Cl And only moderately permeable to urea. Therefore passive absorption of Na and Cl and secretion of Urea takes place which is along their concentration gradients.
- #12 Here, the number of moles of Na plus Cl leaving the lumen exceeds the number of moles of Urea entering due to the greater permeability of tAL to Na and Cl Hence when we consider the osmolality of the Tubular Fluid , it falls slightly below that of the surrounding peri-tubular fluid due to this dissimilar ion permeablity. But this urea re-cycling helps to prevent urea washout from renal medulla, thus contributing to hyperosmotic renal medulla.
- #13 The thick Ascending Limb is peculiar in a way that the permeability to water is negligible while it actively transports Na and Cl from lumen into peritubular space. The urea permeability of TAL is quite low. Urea concentration is considerably greater than that of the plasma and surrounding peritubular fluid. The TF/P remains constant throughout the thick ascending limb in both long and short looped nephrons as the volume of the tubular fluid does not change significantly due to the low water permeability
- #14 We will now see the various active process that take place in the TAL. The first of which and the most important is the Na-K-2Cl which was discovered baby Gamba The Na K ATPase pump plays a crucial role in pumping out Na thus creating a favorable concentration gradient for the Na-K-2Cl co transporter to act. Na is also absorbed into the cell by means of NHE
- #15 A characteristic feature of this absorption is that it is load dependent, meaning the amount of Na reabsorbed will be directly proportional to the Na delievered to it. The active absorption is inhibited by certain prostaglandins and loop diuretics such as frusemide.
- #16 Another type of channels that are active in the basolateral membrane of TAL are the Kidney Chloride Channels. These contain a beta subunit down as the barttin which is essential for the functioning of these channels The chloride entering the cell through the NCCK channels exit the cells through these basolateral channels. Any defect in the genes coding for these proteins or their products as such can lead to various salt losing tubulopathies.
- #17 The potassium entered exits the cell basolaterally but also some amount of Potassium leaks back into the tubular lumen via ROMK Channels This is an important mechanism as it ensures the recycling of K back to the lumen which is essential for salt reabsorption Adding to that they also set a positive trans- epithelial voltage that drives the paracellular reabsorption of 1. Additional Na 2. Other cations such as Ca and Mg
- #18 As pointed out earlier, the absorption of Ca and Mg takes place paracellularly through the tight junctions in the TAL for which activity of channels such as NKCC2 and ROMK act as driving force.
- #19 So to summarize the absorptive functions, the synergistic activity of the main transporters and channels involved in the salt reabsorption together with the integrity of the tight junctions determined by claudins are essential and a prerequisite to prevent electrolyte imbalance.
- #20 We will now move on to the second function of LoH which is the creation of medullary gradient essential for the concentration mechanisms in kidney. 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. An increasing interstitial osmotic gradient is guaranteed by Counter Current System Countercurrent Multiplier System Countercurrent Exchanger System
- #21 Countercurrent System: A system where inflow runs parallel to, counter to, and in close proximity to the outflow for some distance. Countercurrent Multiplier System is formed due to the different transport mechanisms that take place in the U shaped LoH as well as it selective permeability of various segments of LoH. It is responsible for the production of hyperosmolality and gradient in renal medulla. Whereas, Countercurrent Exchanger System is a similar arrangement of the surrounding vasa recta prevents osmotic gradient dissipation.
- #22 In order to understand the counter current multiplier system, we would breakdown to into its component parts ie, the origin of a single effect or the main driving force and the multiplication of that single effect to produce the actual hyperosmotic medulla. The main driving force is the active addition of Na Cl through water impermeable TAL due to the activity of Na K 2 Cl pump in the outer medulla While in the inner medulla, the passive transport of Sodium ions from tAL along with the active transport of the Sodium and Urea from the Collecting Duct into the medullary interstitium produces the single effect The single effect can alone produce a medullary gradient of about 200 osmoles and this effect is multiplied further by the Countercurrent multiplier. This is made possible by the various permeability characteristics of the different limbs of loop of Henle.
- #23 The role of PT in bicarbonate reabsorption is well established Other downstream segments contribute to bicarbonate reabsorption. We will now go on to the role of Loop of Henle in the Acid Base balance. The LoH reabsorbs a significant fraction of the filtered bicarbonate. As the fluid comes down the descending limb, the concentration of bicarbonate increases due to water reabsorption. In the thick ascending limb, the bicarbonate is absorbed through the transcellular pathway It resembles bicarbonate reabsorption in the proximal tubule through NHE3 activity Bicarbonate exit from the cell is mediated by the Cl/ HCO3 exchanger 2 (AE2)
- #24 Urine ammonia excretion derives from renal ammonia genesis rather than glomerular filtration. It is produced from glutamine in the PT as ammonium ion (NH4+) and is released to the luminal fluid. TAL has a crucial role in the reabsorption of amonia via the NKCC2 channels were the ammonia binds at the site for potassium Basolateral exit is mediated by Na NH4 exchange via NHE4, Na -HCO3 Co transporter and a Cl dependent pathway
- #25 Moving on to the applied aspects, we will first see the effect of certain diuretics that act on the Loop of Henle Furosemide, Torasemide, and Bumetanide bind NKCC2 in the TAL in a reversible fashion. The resulting NKCC2 inhibition leads to the reduction in Na+ , K+ , and Cl− absorption This effect overrules the cortico medullar osmotic gradient which in turn increases urine output and also impairs paracellular cations absorption This property has predictable beneficial effects in several conditions, and loop diuretics are the main therapy in fluid retentive states and hypercalcemic conditions
- #26 Bartter's syndrome is an autosomal recessive disorder This is caused by inactivating mutations in the genes coding for the 1Na+/1K+/2Cl− symporter (NKCC2) the apical K+ channel (ROMK) basolateral Cl− channel (ClCNKB) – Classical Barrter This causes the decrease in Na Cl reabsorption and K+ reabsorption by the TAL which in turn causes hypokalemia (i.e., low plasma [K+]) and a decrease in ECFV which activates RAAS mechansim. characterized by hypokalemia, metabolic alkalosis and hyperaldosteronism
- #27 Now coming to the last applied aspect, As we have seen earlier the integrity of the tight junctions is a prerequisite in the reabsorption of Ca and Mg paracellularly. Mutations in the tight junction protein Claudin reduces the permeability of paracellular pathway decreasing their absorption This condition is known as Familial Hypomagnesemic Hypercalciuria and is characterized by enhanced excretion of Ca and Mg and high levels of Ca in urine can lead to nephrolithiasis