Loop of Henle Flashcards
General Loop of Henle
- loop of Henle is shaped in the form of the U and begins at the end of the PT in the outer medulla and descends, as the thin descending limb (tDLH), toward the inner medulla, where it turns and ascends as the thin ascending limb (tALH), back toward the outer medulla, where the tubule epithelial thickens and becomes the thick ascending limb
- the tALH and TAL are relatively impermeable to water and the TAL reabsorbs approximately 25% of the filtered Na+. The TAL effectively dilutes the tubular fluid by reabsorbing Na+ and Cl without reabsorbing water. This decreases the tubular fluid osmolarity below 100 mOsm/L
- active Na and Cl reabsorption occuring the TAL is the solute transport engine driving and maintaining a counter current multiplication of solute concentration difference, or solute concetration gradient, in the interstitium surrounding the LH and the collecting duct, extending from the cortex to the inner medulla.
- in addition to the active reabsorption of Na+ and Cl in the TAL, a process urea recycling in the inner medulla also contributes to the solute concentration gradient in the interstitium, especially when the need arises to defend against plasma volume depletion (dehydration) and/or hyperosmolarity and to excrete a concentrated urine
- thus osmolarity of the medullary interstitium progressively increases upon descending from cortex to the inner medulla and can achieve a maximum value in the inner medulla varying between 600 to 1200 mOsm/L approximately 2-4 fold the osmolarity of the plasma
Reabsorptive solute transport in the TAL
- diluting the tubular fluid osmolarity to values less than plasma and thus, excreting a dilute urine when the plasma volume is expanded and/or hypo-osmotic
- concentrating the tubular fluid osmolarity in the collecting duct by maintaining a gradient of interstitial osmolarity driving reabsorption of water from the collecting duct back into the circulation and concentrating the urine when the plasma volume is contracted and/or hyperosmotic
Antidiuretic hormone (ADH)
- secreted by posterior pituitary in response to changes in plasma osmolarity
- increased plasma osmolarity increases ADH secretion and decreased plasma osmolarity decreases ADH secretion
- ADH increases the water permeability of the collecting duct allowing the osmotic equilibrium of tubular fluid with the interstitium and the peritubular vasculature surrounding the collecting duct
- thus, in the presence of ADH, osmotic equilibration of tubular fluid permits water reabsorption back into the circulation and excretion of a concentrated urine
- in the absence of ADH, the collecting duct is impermeable to water, preventing water reabsorption and therefore, osmotic equilibrium of the tubular fluid, with the interstitium and the peritubular vasculature surrounding the collecting duct does NOT occur, permitting excretion of a dilute urine
Osmolarity of the tubular fluid
- the osmolarity of the tubular fluid in the diluting segment of the nephron is always less than the osmolarity of plasma, in the presence or absence of ADH, regardless or whether volume expanded or volume contracted. The tALH, TAL, DCT is insensitive to ADH and remains water impermeable in the presence of ADH
- the gradient of osmolarity extending from cortex to inner medulla in the medullary interstitium is always present, in the presence or absence of ADH, regardless of whether volume expanded or volume contracted. However the gradient is less steep in diuresis (volume expanded/ decrease plasma osmolarity) than in antiduresis (volume contracted/ increased plasma osmolarity)
- thus, the controlling variable determining excretion of a dilute or concentrated urine is the circulating level of ADH, which modulates the water permeability of the collecting duct and the reabsorption of water from the collecting duct back into the circulation. More water is returned to the circulation (increase ADH) when the plasma volume is contracted and/or hyper-osmotic and less water is returned to the circulation (decrease ADH) when the plasma volume is expanded and/or hypoosmotic
Functional Properties of the Loop of Henle
- Thin descending limb:
- low permeability to solutes (NaCl, urea)
- high permeability to water
- passive tubular fluid-interstitium equilibration of solute and water concentrates the tubular fluid as if descends in the tDLH
Thin ascending limb:
- passive NaCl reabsorption
- relatively water impermeable
- passive urea secretion
Thick ascending limb:
- active NaCl reabsorption via Na/K/2Cl symporter
- relatively water impermeable
- generates and maintains a 200 mOsm/L difference in osmolarity (gradient) between the tubular fluid in the lumen (low) and the interstitium (high)
Transport Mechanisms Mediating NaCl Reabsorption in The TAL
- approximately 25% of filtered sodium and 20% of filtered K is reabsorbed in the medullary and cortical thick ascending limb of loop of Henle
- the process of transcellular sodium and potassium reabsorption from the tubular fluid to the renal vasculature results from the presence and coordinate function of membrane-specific transporters at the luminal (tubular fluid) and basolateral (vascular) side of the TAL cell
- at the luminal membrane a Na+-K+ -2Cl cotransporter mediates the uptake and intracellular accumulations of Na+, K and Cl
- at the basolateral membrane ion-specific channels mediate efflux of intracellular Cl and K and Na+/K ATPase mediates efflux of intracellular Na+
- the presence of K channels in the luminal membrane also mediates efflux of intracellular K back into the tubular fluid which together with Cl efflux across the basolateral membrane generates a lumen positive potential difference across the TAL tubular epithelium
- the lumen positive potential difference serves as a driving force for paracellular Na reabsorption across the TAL tubular epithelium
- Notably, the Na+/K/2Cl cotransporter is inhibited by loop diuretics which decrease reabsorption of Na+, K and Cl and increase excretion of Na+, K, and Cl in urine
- solute transport acorss the TAL epithelial generates a 200 mOSm/L gradient of osmolarity across the epithelia from lumen to interstitium
Countercurrent Multiplication of Solute Concentration Difference
- active reabsorption of Na+ and Cl occuring in the TAL is the solute transport engine driving and maintaining a counter current multiplication of solute concentration difference or solute concentration gradient, extending from the cortex to the inner medulla, in the interstitium surrouding the LH and the collecting duct
- thus, the osmolarity of the medullary interstitum progressively increases upon descending from cortex to the inner medulla and may achieve a maximum value (1200 mOsm/L) approximately 4X the osmolarity of plasma
- the TAL reabsorbs or pushes solute out of the tubular fluid against a gradient of 200 mOsm/L, creating a higher osmolarity outside the TAL in the interstitium
- given the maximum ability of the TAL to pump solute against a gradient of 200 mOSm/L in the outer medulla, what accounts for the 300 mOsm/L to 1200 mOsm/L gradient from cortex to inner medulla achieved during antidiuresis
- the loop of Henle generates and maintains a large cortico-medullary osmotic gradient by a process of countercurrent multiplication or amplifying, 6 fold, the transport capacity of the TAL to pump solute against a 200 mOsm/L difference in transtubular osmolarity
Generation of high Interstitial Osmolarity by Countercurrent Multiplication
- a stepwise process for understanding countercurrent multiplication begins with equivalent interstitial and tubular fluid osmolarities in the descending and ascending limbs. Each of the 5 cycles shown involves 2 steps
- a pumping or reabsorption of solute out of the ascending lumb into the interstitium to a limiting osmotic gradient of 200 mOsm/L and instant osmotic equilibration with the tubular fluid in the opposing descending limb
- an axial advance or shift of fluid forward along the tubule and instantaneous equilibration of tubular fluid in the descending limb and the interstitium
- Pump- Equilibrate- Shift - Equilibrate
Steps of countercurrent multiplication
- Step 1- begins with active NaCl reabsorption in the water impermeable ascending limb generating a 200 mOsm/L difference or gradient between the tubular fluid in the ascending limb and the fluid in the interstitium and descending limb, which is water permeable. Again, the osmolarity of the tubular fluid in the descending limb and the interstitium equilibrates instantly. Thus, the osmolarity in the ascending limb decreases to 200 mOsm/L whereas the osmolarity of the interstitium and decending limb inreases to 400 mOsm/L
- Step 2- begins with the advancement of tubular fluid resulting from introduction of isosmotic (300 mOsm/L) tubular fluid from the proximal tubule in the descending limb. This pushes the column of fluid forward along the loop of Henle decreasing the osmolarity at the beginning of the descending limb and increasing the osmolarty at the beginning of the ascending limb. again, osmotic equilibration occurs, instantly between the interstitium and the fluid at the beginning of the descending limb which reduced the interstitial osmolarity from 400 to 300 mOsm/L
Step 3- is the active NaCl reabsorption out of the ascending limb again generating a 200 mOsm/L difference or gradient, at each transverse level, between the tubular fluid in the ascending limb and the fluid in the interstitium and descending limb. Importantly, in cycle 2 where the 200 mOsm/L difference or gradient of transtubular osmolarity exists at the beginning and end of the ascending limb, the tubular fluid osmolarity is greater at the beginning of the ascending limb in the inner medulla than at the end of the ascending limb in the outer medulla
Step 4- again, the advancement of tubular fluid resulting from introduction of isosmotic (300 mOsm/L) tubular fluid from the proximal tubule into the descending limb and instantaneous osmotic equilibrium between the interstium and fluid in the descending limb. Note, the osmolarity at the beginning of the ascending limb (500 mOsm/L) now exceeds the osmarility at the beginning of the ascending limb (400) in the preceding cycle
Step 5- Repeat these step-wise processes of solute reabsorption against a 200 mOsm/L gradient in the ascending limb, instantaneous osmotic equilibrium of interstitium and the fluid in the descending lumb and fluid advancement. The result is a progressive, step-wise, increase in interstitial osmolarity at the tip or turn of the loop of Henle in the papilla from 300 to 600 mOsm/L. Thus, as shown they kidney generates and maintains a longitudinal osmotic gradient of 300 mOsm/L extending from cortex (300 mOsm/L) to the papilla (inner medulla) (600 mOsm/L). The kidney achieves this by multiplying the effect or transporting solute against an osmotic gradient of 200 mOsm/L in the ascending limb, which is impermeable to water and thus prevents water reabsorption and dissipation of the solute gradient in the interstitium
-Finally in step 7A- of cycle 4 includes, most importantly, the collecting duct, which extends from cortex to medulla surrounded by the interstitual osmotic gradient also extending from cortex to medulla. The water permability of the collecting duct is determined by circulating levels of ADH, which induces an increased reabsorption of water from the tubular fluid into the interstitium and circulation by a process of osmotic equilibrium. The ability of the kidney to defend against dehydration and excrete a concentrated urine or defend against hyperhydration and excrete a dilute urine results from the presence or absence of ADH
Role of Urea Cycling
- Urea is a metabolic end product of muscle and amino acid catabolism
- the renal handling or urea includes a tubule to interstitium and interstium to tubule recycling of urea which contributes to the generation and maintenance of an increased cortico-medually gradient of hyperosmolarity.
- the osmolarity of the inner medulla varies between 1200 mOsm/L during antidiuresis and 500 mOsm in diuresis
- this difference in osmolarity is due primarily to a difference in the amount of urea presence in the interstitial solute osmolarity is due mostly to NaCl, whereas in the deepest parts of the inner medulla, during antidiuresis, approximately 50% of the interstitial solute osmolaritty is NaCl (300 mM = 600 mOsm/ L) and 50% is urea (600 mM = 600 mOsm/L)
Antidiuresis
-increased circulating levels of ADH increase both the water permeability and the urea permeability of the inner medullary collecting duct effectively concentrates urea in the tubular fluid creating an outward urea concentration gradient driving the increased urea reabsorption into the interstitial urea concentration (600) is sustained by increased secretion of urea into the tDLH and tALH where it continues to recycle at elevated concert rations from tubular fluid to interstitium and interstitium to tubule until ADH levels decrease
Diuresis
- decreased circulating levels of ADH decrease both the water permeability and the urea permeability of the inner medullary collecting duct
- in the absence of ADH, the reabsorption of water and urea from the inner medually collecting duct is substantially reduced resulting in increased excretion of water and urea in the urine
- the decreased in urea reabsorption into the interstitium of the inner medulla during diuresis decreases the interstitial urea concentration in the inner medulla to level below 100 mM until circulating ADH again increases
- the absence of urea in the inner medulla decreases the inner medullary interstitial osmolarity to 600 mOsm/L
Cortico-Medullary Urea, Na and Cl Concentration in Antidiuresis
- the change in concentration of Na, Cl and urea in the interstitium as a function of anatomical depth in the kidney from the outside (cortex) to inside (inner medulla)
- note, in this instance of antiduresis, when the kidney is responding to plasma volume depletion and/or plasma hyper-osmolarity, the osmolarity of inner medullary interstium is increased by urea recycling
- the inner medullary interstial osmolarity may be calculated, as shown, as the sum of the Na concentration (300) the Cl concentration (300), the urea concentration (600) or 1200
- in diuresis, when the kidney is responding to plasma volume expansion and/or plasma hypo-osmolarity, the osmolarity of the inner medually interstitial osmolarity may be calculated, in diuresis, as the sum of the Na concentration (300) and the Cl concentration (300) where the urea concentration is essentiall zero or 600
Role of Vasa Recta
- the blood supply or vasculature in the renal cortex and in the renal medulla is segregated allowing solutes reabsorbed from the Proximal Tubule in the cortex to rapidly re-enter the circulation and exit the kidney in the renal vein
- the blood supply surrounding the Loop of Henle, in the medulla, is the vasa recta, and is a specialized vascular anatomy facilitating the countercurrent exchange of solutes between the vasa recta and the interstitium, thus preserving the cortic-medullary gradient of osmolarity and preventing the washout of solute from the medulla. This is achieved by a slower rate of blood flow through the vasa recta, which is peritubular and surrounds the Loop of Henle
Functional Properties of the Vasa Recta and Exchange System
- the vasa recta must supply oxygen and nutrients to and eliminate CO2 and metabolic end products from the Loop of Henle epithelia with compromising the process of counter current multiplicatiion performed by the Loop of Henle in generating and maintaining the cortico-medullary gradient of osmolarity. This is achieved by a vasa recta with a hairpin cortico-medullary anatomy aligned with the cortico-medullary anatomy of the Loop of Henle and a low rate of blood flow throgh the vasa recta
- the vasa recta are permeable to water and small solutes and the passive exchange of permeable solutes and water occurs between the vasa recta and the interstitium as determined by differences in water and solute concentration in the vasa recta and interstitium. In constrast to the active exchange of solute, in the loop of Henle, the vasa recta mediates passive exchange of solutes and water due to its U shaped anatomy and absence of transport activity
- as iso-osmotic vasa recta blood flows down toward the inner medulla (in parallel with descending Loop of Henle) solutes from the interstitium move into the vasa recta and water moves out of the vasa recta into the interstitium. This effect increases the osmolarity of the blood as it descends toward the inner medulla
- as hyperosmotic blood moves up away from the inner medulla towards the cortex, the exchange reverses and solutes move out of the vasa recta into the interstitium and water moves from the interstitium into the vasa recta. This effect decreases the osmolarity of the blood as it ascends toward the cortex
