Loop of Henle and Distal Nephron

Question 1

Cortical and juxtamedullary

Answer 1

Cortical will never get into the inner medulla

Juxtamedullary nephrons are deeper in the cortex and go into the medulla

Question 2

Osmolarity as you go from cortex to medulla

Answer 2

INcreases as you move from border to papilla tip

Hypertonicity created by increasing amounts of NaCl and urea

Interstitial hypertonicity essential for urine concentration

Question 3

Thin descending Henle loop

Answer 3

Reabsorb H2O…does NOT reabsorb NaCl (or other solutes)

Osmolarity increases as it flows toward the papilla due to water reabsorption

Osmolarity of the interstitium will keep increasing which favors water flow OUT…will become isotonic to interstitial fluid at the bottom

Question 4

Ascending limb

Answer 4

Avidly reabsorbs NaCl and NOT H2O

Generates hypotonic fluid (so diluting segment of the nephron)

Question 5

Mech of NaCl reabsorption in the thick ascending limb

Answer 5

Dependent of Na-K-ATPase on basolateral membrane

Transport into cell across the luminal membrane via Na-K-2Cl- co-transporter

Reflux of entering K into tubular lumen via a K+ selective channel…ensures adequate supply of K for Na-K-2cl cotransporter AND generates lumen-pos potential which provides driviing force for paracellular transport of multiple cations

On basolateral membrane, also Cl channels and K-Cl symporters

Question 6

Trnasporter terminology of thick ascending limb

Answer 6

NKCC2 - Na-K-CL on lumen

ROMK - luminal K channel

Basolateral K-Cl cotransporter - KCC4

Basolateral Cl channel - CLC-NKB

Question 7

Modulators of NaCl reabsorpiton in thick ascending limb

Answer 7

GT balance…increased delivery of NaCl - reabsorption increases

Adrenal insufficnet - less urine diluting and concentrating

Reabsorption increeaed by - ADH, insulin, glucagon, isoproterenol

Decreased by aterial natiuretic peptide, adenosine, dopamine, bradykinin

Na-K-Cl transporter inhibited by loop dirutertics

Bartter’s syndrome

Question 8

Transport in the distal neprhon

Answer 8

Consists of DCT and collecting tubule

Distal delivered about 10% of filtered H2O and 10% of NaCl

Distal neprhon transport of H2O regulated by ADH…more ADH, more H@O reabsorption, decreased excretion

Transport of NaCl regulated by aldosterone…increased aldosterone, increased NaCl reabsorption, decreased NaCl excretion

Question 9

ADH regulation of distal neprhon

Answer 9

In presence of ADH, collecting tubule permeable to water

Favorable osmotic gradient promotes water reabsorption…thereby generating a small volume of hypertonic urine

Without ADH, impermeable…reabsorption of some NaCl continues to dilute the tubular fluid…this means excretion of large amount of hypotonic urine (diuresis)

Question 10

Intracellular mech of ADH

Answer 10

Reabsorption of water by collecting tubule system depends on presence of aquaporins in luminal membrane

ADH stimulates insertion of AQP-2 channels into luminal membrane
Increased cAMP, increased translocation of channel-containing vesicles ot luminal mebrane, increased fusion and insertion (like exocytosis), increased water permability

Decreased ADH - vesicle retrieval by endocytosis

AGP-3 channels only on the basolateral membrane

Question 11

The aquaporins

Answer 11

All nephrons express basolateral aquaporins

Lack of LUMINAL aquaporins explains water impermeability of the ascending limb (this is where main regulation is ocurring)

Question 12

NaCl reabsorption in DCT

Answer 12

Reabsorbs NaCl via luminal NCC (Na-Cl co-transporter)

Cl- exits basolaterally by KCC4 (K-Cl co-trnasporter) and CIC-Kb (Cl- channel)

Thiazide diuretics target NCC

Question 13

NaCl reabsorption in collecting tubules

Answer 13

Absolute dependence on Na-K-ATPase located on basolateral

Na enters via luminal membrane Na selective channels (ENaC)

Question 14

Aldosterone regulation of NaCl

Answer 14

Controls in cortical collecting tubule

Increases number of luminal membrane ENaC channels

increase Na-K-ATPase

INcrease krebs cycle enzymes synthesis therefore more ATP and more ATPase activitiy

Question 15

Aldosterone mech

Answer 15

Binds intracellular to mineralcroticoid receptor but cortisol also has similar bidning

Higher levels f cortisol prevented from affecting Na reabsorption due to 11beta hydroxysteroid dehydrogenase type 2…converts cortisol to cortisone

INhibiton of enzyme activity can lead to NaCl retention and HTN

Question 16

Sodium deposition in the interstitium

Answer 16

Depostion of NaCl by countercurrent multiplication

Maximal NaCl concentration difference across ascending limb is not fantastic…this can move paracellularly back to the tubular lumen

If then only isotonic fluid flowed into the ascending limb, would be impossible to maintain interstitial NaCl concentrations about 150

H2O reabsorption by thin descneding limb delivers hypertonic fluid to the ascening…this promotes deposition of high concentrastion of NaCL in the interstitium

Question 17

Countercurrent multiplication

Answer 17

Reabsorption of NaCl by ASC and retention in INT

Osmotic gradient created promotes H2O reabsorption from the descneding limb

Additional isotonic fluid enters DES from proximal tubule

Repeating multiple cycles generates a vertical osmotic gradient but at any horizontal level, only a 200 mOsm/L gradient across the ASC

Basically gradient stays the same but absolute values change

Question 18

Urea recylcling

Answer 18

Cortical/out medullary collecting tubule cannot reabsorb urea thereofre with ADH…TF urea concentration increases (increase ADH..increase H@O reab…increase TF urea ())

As TF flows into inner medullary collecting tubule, high urea concentration promotes facilitated reabsorption into INT via UT-A

ADH also increases permability of this segment to urea b increasing transporter expression

Some urea will diffuse back into thin descneing and ascending limb but in the presence of ADH, this will be re-concentrated and reabsorbed

But decrease ADH…decreased urea…decreased reabsorption…increase urea excretion…decrease medullary osmolarity

Question 19

ADH control

Answer 19

Decrease ADH, derease urea reab, decrease medullary interstitla urea, decrease medullary osmolarity

Decrease medullary osmolarity, decrease thin descending H2O reabsoprtion

Decrease ascending limb NaCl reabsorption, decrease interstitial NaCl, decrease medullary osmolarity

If ADH increases, more urea and NaCl redesposited and increased medulary osmolarity

Question 20

Cell survival in hypertonic environment

Answer 20

With deposition of more INT NaCl and urea (due to more ADH), medullary cells should shrink due to efflux

Short term - cells volume regulate…RVI due to influx of Na, K, and Cl…increased intracellular osmolarity..osmotic H2O influx

This altered intracellular ionic compositon not sustainable LT

Longer terms - cells accumulate organic osmolytes to maintain volume and restore ionic strength

INcreased TonEB

Increases syntethics of sodium myo-inositol (SMIT)
NaCl-betaine (BGT1)
NaCl- taurine (Tau1)

Also increases synthesis of aldose reductase (sorbitol) and neuropathy target esterase (glycerophosphorylcholine)

Question 21

Seocnd problem with hypertonicity

Answer 21

Deposition of urea required for generation of hypertonic interstituum but urea diffuses into cells and disrupts intracekllular protein structure/function…solution - betaine and GPC protect cellular proteins

Question 22

Other TonEB effects

Answer 22

Increased HSP synthesis (urea protectant)

Increased UT-A synthesis (promotes urea reabsorption)

Increased AQP2 syntehsis

Question 23

Brain volume regulation

Answer 23

Increase ECF osmolarity…initial decrease and regulatory increase

Acute adaptation followedb y longer term

Question 24

Countercurrent exchange

Answer 24

Medullary blood supply essential

As isotonic plasma flows into medulla, normally the sodium chloride and urea would diffuse into capillaries and could reduce meduallry hypertonicity

CE in the vasa recta preserves the hypertonic gradient in the medullary interstitum

Question 25

Plasma leaving the medulla

Answer 25

Has higher osmolarity than that entering

Exiting flow rate higher than entering

INdicative of important function of vasa recta to
1) remove all water reabsorbed by descending limbs and medullary collecting tubules and remove most of NaCl reabsorbed by ascending limb

Solute in on the downhill, solute out on the uphill