Loop of Henle and Distal Nephron Flashcards
Cortical and juxtamedullary
Cortical will never get into the inner medulla
Juxtamedullary nephrons are deeper in the cortex and go into the medulla
Osmolarity as you go from cortex to medulla
INcreases as you move from border to papilla tip
Hypertonicity created by increasing amounts of NaCl and urea
Interstitial hypertonicity essential for urine concentration
Thin descending Henle loop
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
Ascending limb
Avidly reabsorbs NaCl and NOT H2O
Generates hypotonic fluid (so diluting segment of the nephron)
Mech of NaCl reabsorption in the thick ascending limb
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
Trnasporter terminology of thick ascending limb
NKCC2 - Na-K-CL on lumen
ROMK - luminal K channel
Basolateral K-Cl cotransporter - KCC4
Basolateral Cl channel - CLC-NKB
Modulators of NaCl reabsorpiton in thick ascending limb
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
Transport in the distal neprhon
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
ADH regulation of distal neprhon
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)
Intracellular mech of ADH
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
The aquaporins
All nephrons express basolateral aquaporins
Lack of LUMINAL aquaporins explains water impermeability of the ascending limb (this is where main regulation is ocurring)
NaCl reabsorption in DCT
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
NaCl reabsorption in collecting tubules
Absolute dependence on Na-K-ATPase located on basolateral
Na enters via luminal membrane Na selective channels (ENaC)
Aldosterone regulation of NaCl
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
Aldosterone mech
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
Sodium deposition in the interstitium
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
Countercurrent multiplication
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
Urea recylcling
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
ADH control
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
Cell survival in hypertonic environment
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)
Seocnd problem with hypertonicity
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
Other TonEB effects
Increased HSP synthesis (urea protectant)
Increased UT-A synthesis (promotes urea reabsorption)
Increased AQP2 syntehsis
Brain volume regulation
Increase ECF osmolarity…initial decrease and regulatory increase
Acute adaptation followedb y longer term
Countercurrent exchange
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
Plasma leaving the medulla
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
