Lecture 8: Transport in the Distal Nephron Flashcards
What is the character of fluid entering the thin limb of Henle’s Loop?
- Na is same as concentration as plasma
- Cl in higher concentration compared to plasma due to HCO3 reabsorption in PT
- because of HCO3/Cl antiporter
- No glucose, AA or protein (unless diseased states)
- Rich in K as it is secreted into the pars recta (PST)
- Rich in NH4+ as it is synthesized in the PT
How much active transport activity is present in the THIN limbs of LoH?
Not a lot of active transport taking place
Mostly passive
Hardly any Na/K ATPase in thin descending and ascending loops
Where is Na/K ATPase activity lowest?
In the descending and ascending loops of LoH
What is the distal nephron?
Everything after the pars recta is considered the distal nephron
What is the function of the thin limbs of LoH?
- Descending thin limb epithelium is permeable to water but has a low permeability to Na and Cl
- Allows water to be extracted from the tubule fluid as thin limb descends
- Leads to hypertonic interstitium of medulla
- Ascending thin limb is largely IMPERMEABLE to water
- highly permeable to Na and Cl
- causes salt to diffuse out of the tubule
What is the INTEGRATED function of the thin limbs?
To reabsorb water and sodium isotonically that is in about same net concentration as Na/water in blood or glomerular filtrate
Allows one to reabsorb both the water and salt components of blood
What is the tubular fluid content by the end of the thin limbs?
A. 75% of filtered NaCl reabsorbed -60% in PT -15% in thin limbs B. 75% of filtered water reabsorbed -60% in PT -15$ in thin limbs C. 90% of filtered potassium is reabsorbed (although there is still a lot of K because of K secretion) D. 100% of filtered glucose reabsorbed E. 90% of filtered phosphate reabsorbed F. 20% of filtered magnesium reabsorbed G. 100% of filtered HCO3- reabsorbed
What is the function of the thick ascending limb?
- Powerful NaCl transporter to dilute the urine
- Water impermeable
- Lumen positive potential difference vs blood side of tubule
What is the key transporter for thick ascending limb function?
The NKCC2 transporter
NKCC2 = Na-K-2Cl symporter
So brings in 1 mol of Na and K and 2 mol of Cl into the lumen
NKCC2 transporter has no limit as to how much sodium they can reabsorb
Why are furosemide diuretics (the ones that block NKCC2) so poor?
Because even though they block most NKCC2 channels, they don’t block them all
The transporters remaining have no saturation point so can take up as much solute as they see
What are the characteristics of the transporters in thick ascending limb?
- NKCC2 absorbs Na-K-2Cl and has no saturation point (can take up as much as comes by)
- There exists a ROMK (renal outer medullary potassium) channel on the apical membrane of thick ascending limb
- ROMK pumps potassium (absorbed into lumen by NKCC2) back into the lumen
- Mg2+ and Ca2+ will go into the lumen because of K+ leaving the lumen
- ROMK thus creates the electric gradient necessary for Ca and Mg to enter the cell
- there exists CLC-Kb/CLC-Ka channels on basolateral membrane that pump Cl- into circulation and away from the lumen
What happens to urinary calcium excretion when a patient has a defect in Renal Outer Medullary Potassium (ROMK) transporter?
Increased urinary calcium excretion because there is less of an electrogenic gradient
What ions are excreted in greater volume due to furosemide ?
Increases excretion of Na by blocking NKCC2
Also increases excretion of Ca and Mg because + charges stay in the lumen (K is not absorbed)
What is the character of reabsorption in THICK ascending limb of henle?
The diluting section of the kidney 25% of filtered NaCl is reabsorbed 0% of filtered water is reabsorbed (ABSORBS NO WATER) 20% of filtered calcium reabsorbed 0% of glucose, Pi and HCO3- reabsorbed 70% of Mg reabsorbed 90% of synthesized NH3 reabsorbed
What are the consequences to patient with defect in thick ALH?
- failure to thrive (volume depletion)
- Low BP (volume depletion)
- Hypokalemia (No potassium uptake by NKCC2)
- Calcium deposits in the kidney (because not enough Ca uptake)
- High alkali content of the blood
-depletion of ECF volume = increased aldosterone secretion
-high aldosterone = increased K and H+ EXCRETION so less K and H in body
-that’s why you get hypokalemia and excess alkali in body
Receptors are all fucked inthis case
What is the normal character of fluid entering the distal tubule?
- Hypotonic due to powerful NaCl reabsorption in thick ALH
- Dilution due to concomitant H2O impermeability in thick ALH
- Very little K and NH4
- No HCO3-
- Moderate amount of Ca and Mg
- About 10% of filtered NaCl
What is the distal tubule made up of?
Early DCT or DCT1
Late DCT or DCT2
Connecting Tubule or CNT
Experiments show that transporters can change to meet body demand but more research required
What is the nature of distal nephron transport?
- steep chemical gradients established between lumen and cell/blood
- Hormonally regulated transport pathways serving systemic needs
- Separate pathways for sodium and other ion transport systems although sodium dependence often present
What is the key apical membrane transporter in the DCT?
The NCCT (Na-Cl cotransporter)
Na-Cl symporter
Takes up 5% of sodium
Blocked by thiazide
What is the membrane potential at the DCT?
Slightly positive because of Cl- being reabsorbed
At the basolateral membrane and K+ cycling
Where does Active Mg2+ absorption take place?
DCT1 and DCT2
Where does active Ca2+ absorption take place?
DCT2 and CNT (connecting tubule)
What region of the DCT actively absorbs both Ca and Mg?
DCT2
What is the mechanism of Mg2+ reabsorption?
In DCT1 and DCT2, TRPM6 lets Mg diffuse Down its gradient Gradient is established by efflux of K Cells through Kv1.1 channel into the lumen Efflux of K cells means intracellular is Slightly negatively charged NCC transporter is isoeletric
What is TRPM6?
Transient Receptor Potential Magnesium
Ion channel
What is EGF?
Epidermal growth factor
The first magnesiotropic hormone to regulate Mg2+ reabsorption through the TRPM6
EGF stimulates Mg reabsorption by activating the TRPM6
What is the significance of HNF1B?
Stands for hepatocyte nuclear factor 1 homeobox B
Regulates the function of the Na/K ATPase by determining its expression
What is the mechanism of Ca absorption?
In DCT2 and CNT, 3 steps occur 1. entry of luminal Ca via the TRPV5 channel on apical membrane 2. Calbindin (CaBP) buffers Ca and Ca diffuses to basolateral membrane 3. Ca is extruded by PMCA1b and NCX1
What regulates calcium absorption
At the distal tuble?
Calciotropic hormones like
PTH and 1,25(OH)2D3
What is the significance of calbindin
In the active transport absorption of calcium, it serves to buffer the calcium levels…too much calcium = apoptosis or worse
What is PMCA?
Plasma membrane Ca ATPase
What is NCX?
Sodium calcium exchanger
What is 1,25(OH)2D3?
1,25 vitamin D or calcitriol
Promotes calcium absorption
PTH also promotes calcium reabsorption
PTH upregulates expression of vitamin D
What is the character of fluid leaving DCT?
- Hypotonic
- Less sodium and chloride
- Little if any potassium
- Minimal calcium and magnesium (close to final urine amounts)
- Acidic (because no bicarb)
What is the MRCT?
Medullary ray collecting tubule
Yellow = Distal Tubule
Blue = collecting duct
What is the principal cell in the CCD (cortical collecting duct) epithelium?
One of two cell types of collecting duct
ENa is located in apical surface of principal cell
Na/K on basolateral membrane
K channel on both apical and basolateral membrane to pump K out
Sodium transport with steep gradients
What are the two cell types in collecting duct?
- Principal cell (as seen below)
- Intercalated cells)
- alpha intercalated cells
- beta intercalated cells
What is the function of alpha intercalated cells?
Secretes bicarbonate via pendrin (a specialized apical Cl/HCO3-)
Absorbs Acid through basal H+ATPase
What are the effects of aldosterone? Consequences?
Upregulates ENac and the Na/K ATPase in collecting duct
Stimulates Alkalosis and hypokalemia (potassium wasting!)
Because so much Na is taken up, you have to counter that with excreting potassium
H/K antiports also work harder so you lose H+ as well
What are the clinical consequences of excess sodium transport
- Hypertension (volume expansion)
- Hypokalemia
- Alkalosis
What is potassium wasting?
When you excrete too much potassium and have hypokalemia
What is Liddle’s syndrome?
A syndrome in which there is a gain of function in the ENaC leading to too much sodium absorption
What are the two causes of excess sodium transport from the collecting tubule?
- hyperaldosteronism
2. Liddle’s syndrome (gain of function of ENaC)
Why do H+ ions get secreted into the lumen during sodium excess?
Because chloride ions are taken up much more slowly from the lumen
Therefore this “lag” creates a temporary electric gradient that forces H+ towards the lumen, thereby depleting the cell of H+ and leading to alkalosis
Where do H+ ions come from?
The combination of H2O and CO2 to form HCO3- and H+
What are the intercalated cells?
The cells in collecting duct that produce H+
One of the two cell types of collecting duct
What are the functions of collecting duct?
- Regulates the final urine composition for sodium, potassium and bicarb or H+
- Allows water retention or elimination depending on needs of the organism
- Allow the formation of a high osmolality in the renal interstitium so that concentration of the urine is possible
