Renal Module: Loop of Henle & Vasa Recta

What transport protein is critical for the function of the loop of Henle? Where is it found?

NKCC2 (sodium-potassium-2-chloride) co-transporter - Found only in salt-transporting epithelia

How is the movement of solutes at the ascending limb affected by location?

NKCC2 adds Na⁺ and Cl⁻ as primary electrolytes into the interstitium. - Occurs in a nonlinear fashion - More solute is moved in one location in the ascending limb than at another location.

Define counter-current exchange.

The passive exchange of contents between two adjacent flowing bodies that are flowing in opposite directions.

Why may the sequence in which functions take place within the loop of Henle be considered counterintuitive?

- Although filtrate flows through the descending limb first and then through the ascending second, the initial functions occur at the ascending limb. - Functions of the descending limb are mostly passive and occur in response to what is happening at the ascending limb.

Explain the counter-current exchange mechanism that occurs with the vasa recta at the loop of Henle.

- Blood flows in from the PCT at a normal osmolarity (300 mOsm/L). - Vasa recta is fenestrated, so it is permeable to both water and solute. - As blood flows into this solute gradient, the solute concentration is greater in the interstitium than in blood, causing fluid movement. - Solute concentrations in the interstitium increase as you go further down the descending vasa recta. - As blood flows down the descending vasa recta, water and solutes are constantly entering and exiting the vasa recta. - Once blood reaches the bottom, solute concentrations in the blood and interstitium are close to equal due to equilibration. - As blood flows up the ascending vasa recta, the interstitium is becoming less and less concentrated. - Leads to solute exiting the vasa recta back into the interstitium and water entering the vasa recta from the interstitium (water conservation).

List some conditions for which a loop diuretic such as Lasix is a common treatment.

- Congestive heart failure (caused by high BP) - Hypertension (excess blood volume) - Pulmonary edema (excessive build up of ECF)

Describe the overall adaptive significance of the loop of Henle.

- Generates corticomedullary solute gradient. - Maintains gradient while delivering O₂ and nutrients with the vasa recta. - Gradient is essential to water conservation that largely occurs at the collecting duct.

Explain the importance of the counter-current exchange mechanism that occurs at the loop of Henle.

- If the descending vasa recta just kept going and exited the kidney instead of going back up, blood would lose A LOT of water and gain a lot of solute. - Instead, blood flows back up and (mostly) "undoes" everything that occurred in the descending limb. - Causes counter-current trapping (the two limbs are exchanging contents, but nothing is being removed from the overall system). - Counter-current trapping allows for the medullary interstitial gradient to be left in place. The loop of Henle exists to conserve water; we wouldn't be conserving water if we kept washing it away.

How does a loop diuretic like Lasix achieve its diuretic function?

- Much of what occurs at the loop of Henle is for the purpose of conserving water at the collecting duct. - Lasix blocks the NKCC2 co-transporter. - Blocking NKCC2 blocks the movement of Na⁺ and Cl⁻ into the interstitium. - Blocking this ion movement minimizes the corticomedullary solute gradient, which is essential for water conservation at the collecting duct. - Minimizing the corticomedullary solute gradient limits the osmotic gradient that drives water removal (reabsorption) from other sections of the nephron. - More water remains in the nephron. - Large drop in extracellular fluid volume. - Urine production is increased.

Describe the potential downside of the counter-current exchange mechanism.

- On top of reabsorption, blood vessels are also for nutrient and O₂ delivery. - Relatively high Po₂ blood enters the descending vasa recta and flows very close to the ascending vasa recta, which has much lower Po₂. - Due to the close proximity and significant difference in Po₂, O₂ will jump from the descending vasa recta to the ascending vasa recta. - This results in the inner portion of the renal medulla being hypoxic because high Po₂ blood is skipping across to the ascending limb rather than flowing all the way down and around, where it would deliver O₂ to the inner medulla. - Due to the hypoxic conditions, the inner medulla is VERY sensitive to any reduction in blood flow. - This is why one of the main problems that people experience when they have dramatic reductions in cardiac output is renal failure.

What is the function of the loop of Henle in cortical nephrons?

- Reabsorption of NaCl and other cations, as well as H₂O.

List the general steps involved in counter-current multiplication at the loop of Henle.

1.) Begins with no gradient. 2.) Ascending limb single effect concentrates the interstitium. 3.) Water leaves the descending limb, concentrating the tubular fluid in the descending limb. 4.) Interstitial gradient begins to develop. 5.) Repeated single effects result in tiers/levels of solute concentration in the tubular fluid.

Name the two types nephrons.

1.) Cortical nephrons 2.) Juxtamedullary nephrons

Describe the first step of the counter-current multiplication process.

Begins with no gradient. - Fluid enters the loop of Henle from the PCT. - PCT reabsorbs isosmotically. - Blood is normally 300 mOsm/L, and since the PCT reabsorbs isosmotically, the blood entering the loop of Henle is still 300 mOsm/L.

What initiates the transport of contents at the loop of Henle?

Active transport of Na⁺ out of the cell into the interstitium and K⁺ into the cell via Na⁺-K⁺ pump (as always).

Describe the second step of the counter-current multiplication process.

Ascending limb single effect concentrates the interstitium. - Ascending limb begins to pump salt (NaCl) into the interstitium, generating a single effect. - Solute concentration in the interstitium is now higher than in the descending limb. - Osmotic gradient is now established.

What are the anatomical differences between cortical nephrons and juxtamedullary nephrons?

Cortical nephron: - A majority of the nephron is located in the renal cortex (outer layer of the kidney). - Often referred to as short-looped nephrons because they have a relatively short loop of Henle that only extends into the renal medulla a little bit. Juxtamedullary nephron: - Has an extremely long loop of Henle that extends deep into the renal medulla.

Explain how the loop of Henle is a counter-current multiplier.

Counter-current = Ascending and descending loops flow next to each other and in opposite directions. Multiplier = Very active process (uses energy). The process of actively transporting solutes into the interstitium at the ascending loop to generate a solute gradient in the interstitium and tubular fluid.

Explain how the counter-current exchange mechanism of the loop of Henle can actually contribute to renal failure in the event of dramatic decrease in cardiac output.

Hypoxic conditions in inner medulla result in high sensitivity to reductions in blood flow. Example: - Someone has a heart attack and needs some sort of heart surgery. - For a couple hours, cardiac output is dramatically reduced for the operation. - The next day, the person experiences renal heart failure. - During the time when cardiac output was reduced, the kidney was hypoxic, making the inner medulla even more hypoxic. - Due to the increased hypoxia, medullary nephrons begin to die off, to a degree. - Medullary nephron death leads to renal failure.

Describe the fourth step of the counter-current multiplication process.

Interstitial gradient begins to develop. - Ascending limb continues to pump NaCl out into the interstitium. - Tubular fluid will be more concentrated at the bottom of the ascending limb because that fluid is just beginning to have solute removed, whereas fluid further up has already a lot of solute. - Generates tiers of solute concentration.

Since counter-current exchange involves basically undoing everything in the ascending limb that was done in the descending limb, then is blood osmolarity when it leaves the loop of Henle the same as when it entered? What are the implications of this?

Not quite. - The blood does gain some solute between when it enters the loop and when it exits. - Blood entering the loop typically has an osmolarity of ~300 mOsm/L. - Blood exiting the loop typically has an osmolarity of ~325 mOsm/L. - This means that the loop of Henle has to continually put more solute back into the interstitium in order to maintain that interstitial gradient.

What are vasa recta?

Peritubular capillaries located in the renal medulla.

Describe the fifth step of the counter-current multiplication process.

Repeated single effects result in tiers/levels of solute concentration in the tubular fluid. - Tubular fluid becomes more concentrated as it flows down the descending limb because water is leaving. - Tubular fluid becomes less concentrated as it flows up the ascending limb because NaCl is being pumped out. - Bottom of loop = very concentrated; NaCl is pumped out of the lower portions of the loop because there is more to pump out. - Generates gradient in the interstitium that is low (300 mOsm/L) at the top and high (max. 1200 mOsm/L) at the bottom.

Explain the function of NKCC2 co-transporter in the transport of contents at the loop of Henle.

Secondary active transport (driven by Na⁺ gradient). - Moves Na⁺, K⁺, and two Cl⁻ ions from the tubular fluid into the cell. (The transport of two cations and two anions maintains an electroneutral environment). - The Na⁺ delivered into the cell by the NKCC2 co-transporter supplies the Na⁺ for active transport into the interstitium. - The K⁺ delivered into the cell can then leak back out (the K⁺ gradient generated favors flow out of the cell at the apical and basolateral membranes). - Some K⁺ leaks back out into the lumen, some is reabsorbed by the vasa recta, and some from the lumen moves to the interstitium paracellularly. - The Cl⁻ that is delivered into the cell by NKCC2 generates a gradient that drives the passive flow of Cl⁻ into the interstitium through a channel. The back-leak of K⁺ into the tubular fluid via leak channels causes the tubular fluid to become electropositive (net change of two anions and one cation leads to growing positive charge). - Acts to repel other cations. - Occurs more toward the end of the ascending limb after a lot of transport has already occurred and K⁺ accumulates in the tubular fluid. - Cation repulsion due to K⁺ accumulation in the tubular fluid drives reabsorption of other cations into the vasa recta. - Major site of Mg²⁺ and Ca²⁺ reabsorption.

Why are loop diuretics often misused in athletics (particularly in combat sports)? What makes it dangerous?

Taking loop diuretics is an easy way to lose 10 lbs in a single day. - Fighters will take loop diuretics to drop weight rapidly in order to make weight. - It is dangerous because abuse can upset osmolarity and electrolyte gradients.

What permeability characteristic of the ascending limb is critical to its function?

The ascending limb is has very low permeability to water. - Water movement would dilute interstitial solute concentrations. - For proper loop of Henle function, the interstitium needs to be concentrated with solute.

Define "single effect."

The difference between concentration inside the loop and the concentration in the interstitium at any single location.

What is the most important function of the loop of Henle? What type of nephron performs this function?

WATER CONSERVATION - Juxtamedullary nephrons

Describe the third step of the counter current multiplication process.

Water leaves the descending limb, concentrating the tubular fluid in the descending limb. - Descending limb is permeable to water. - Water moves down its osmotic gradient into the interstitium. - Tubular fluid in the descending limb becomes more solute-concentrated. - The more concentrated tubular fluid then enters the ascending limb.