Physio Renal Transport II (39)
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What would happen if after a meal, the K+ taken up by gut the & delivered to plasma just stayed there?
- extracellular K+ would increase dramatically (b/c 98% of body K+ is intracellular) & would lead to nerve misfiring & cardiac arrhythmias
- after a meal, K+ is rapidly taken up into cells by Na+/K+ ATPases
- insulin & aldosterone ↑ activity of these ATPases which already use K+ as a substrate so all that needs to be done is to increase their activity
What is the typical dietary K+ intake per day?
- 100 mEq K+/day
- [K+] in extracellular fluid & plasma is ~4 mEq/L
- nearly all (92%) K+ ingested is excreted by kidney
How much K+ reabsorption is occurring in the proximal tubule & by what route?
- ~2/3 (67%) of filtered K+ is automatically reabsorbed in the proximal tubule
- all that K+ reabsorption is occurring via paracellular transit; there is NO transcellular reabsorption
- this is b/c there’s a transepithelial luminal positive membrane potential driving K+ (as well as other cations) to be taken up into the interstitium
How much K+ reabsorption is occurring in the thick ascending loop of Henle & by what route?
- 20% of filtered K+ is automatically reabsorbed here via a transepithelial route using the Na+/K+/2Cl- Cotransporter
- as in the proximal tubule, here there is also a transepithelial luminal positive membrane potential driving paracellular K+ transport into the interstitium
- K+ then exits the epithelial cells into the interstitium via K+ channels on the basolateral membrane
How much K+ reabsorption is occurring in the late distal tubule & collecting duct & by what route?
- 12% can be reabsorbed in the late distal tubule & collecting duct via apical H+/K+ ATPases on intercalated cells
- this is a way of scavenging the last bits of K+ that would otherwise be excreted in the urine
- (this system is only working if you have a K+ depleted state)
What happens to K+ reabsorption & secretion by the renal tubule in the normal & K+ excess states?
- reabsorption in the proximal tubule & thick ascending limb of the loop of Henle occurs as before (not regulated, so ~87% of K+ is 1st reabsorbed)
- however the late distal tubule & collecting duct now show net K+ SECRETION rather than reabsorption
- 15-80% of K+ gets excreted in the urine
- therefore it is the cells of the late distal tubule & CD responsible for K+ regulation
What are the keys cells responsible for this K+ regulation?
- the Principle Cells of the late distal tubule & CD
- these cells contain apical K+ channels that provide a route by which K+ can be secreted into the tubule
What controls how much K+ is being secreted by these Principle Cells?
- 1. how many K+ channels are present on a cells apical membrane & how active they are
- 2. amount of Na+/K+ ATPase activity: more activity, the more gets pumped in, the bigger the gradient, the bigger the driving force to drive K+ OUT into the renal tubule lumen
- however the main determinant of K+ secretion is the plasma concentration of K+, which affects Aldosterone, which affects both K+ & Na+ channel activity, as well as Na+ delivery to principle cells
How does an temporary increase in K+ plasma concentration cause increased activity of apical Na+ channels?
- ingesting a meals causes a transient rise of K+
- that stimulates the release of aldosterone
- aldosterone stimulates the activity of basolateral Na,K ATPase activity in principle cells, which in turn increases the activity of apical K+ channels AND Na+ channel activity*
Why would increased Na+ channel activity help cells secrete K+?
- more Na+ channel activity means more Na+ is entering the cell from the tubular lumen, leaving the inside of the lumen “less” positively charged
- this decrease in + charge in the tubular lumen means it’s EASIER for K+ to leave cells & enter the tubule lumen to be positively charged there
- ↑ Na+ reabsorption into principal cells → ΔΨ (membrane potential) across lumenal membrane becomes less lumenal positive → ↑ K+ SECRETION
Effect of Loop Diuretic (Furosemide) on K+ Excretion
- Furosemide inhibits the apical Na+/K+/2Cl- Cotransporter in the thick ascending limb of loop of Henle
- it inhibits K+ uptake into epithelial cells so that will leave more K+ in the lumen → more K+ will be excreted in the urine → is a “K+ wasting” diuretic
- it also inhibits Na+ uptake in the thick ascending limb, which means more Na+ is left in this initial part of the tubule
- as a result more Na+ gets delivered to the Principle cells of the late distal tubule & CD → ↑ Na+ channel activity → ↑ K+ secretion in this part of the tubule (the principle cells)
- a disease in which Na/K/2Cl cotransporter is defective
- is characterized by hypokalemia b/c K+ is being excreted in the urine
Effect of Thiazide Diuretics on K+ Secretion
- Thiazide inhibits the apical Na+/Cl- Cotransporter in the early Distal Tubule (so Na+ uptake is inhibited)
- this ↑ Na+ delivery to the principal cells (in the late DT/CD) → ΔΨ across apical membrane less lumenal postive → ↑ K+ secretion
- therefore Thiazide diuretics are also K+ wasting
What causes Gitelman’s syndrome?
- a defect in the Na+/Cl cotransporter of the early distal tubule
- as w/ Thiazide diuretics there will be ↑ Na+ delivery to principal cells (in late DT/CD) → ↑ K+ secretion
- Gitelman’s syndrome is characterized by hypotension (due to increased excretion of NaCl b/c it’s less well reabsorbed) & hypokalemia
Effect of Amiloride on K+ Secretion
- Amiloride ↓ activity of Na+ channels in principal cells of the DT/CD
- this also has the consequence of leaving more Na+ in the tubule, however this Na+ CAN’T get into the principle cells → ΔΨ across apical membrane MORE lumenal postive→ opposes K+ secretion across apical membrane → ↓ K+ secretion
- therefore Amiloride is a “K+ sparing” diuretic
Is Liddle’s Syndrome characterized by hypokalemia?
- this syndrome INCREASES the activity of Na+ channels in the DT/CD
- this would greatly increase K+ secretion, making hypokalemia a characteristic of this disease
Ca2+ Function & Distribution
• Ca2+ is crucial for bone formation (bones contain 99% of total body Ca2+)
• 1% of total body Ca2+ is intracellular (primarily in ER & mitochondria or in the SR of muscle cells)
• cytoplasmic Ca2+ functions in signaling, muscle contraction, neurotransmitter release & is maintained at sub-μM concentration
• 0.1% of total Ca2+ is extracellular (~5 mEq/L)
• we typically absorb ~200 mg Ca2+ (10 mEq)/day from the gut - this must be balanced by excretion in urine
• ~540 mEq Ca2+/day is filtered
• 40% of plasma Ca2+ is bound to proteins & therefore NOT filtered across the glomerulus
Ca2+ Reabsorption Along the Renal Tubule
- 70% is reabsorbed in the proximal tubule
- 20% is reabsorbed in the thick ascending limb of the loop of Henle
- 7% by DT
- 1% by CD
- 98% of filtered Ca2+ is reabsorbed; only 2% excreted in urine (will be variable depending on amount of Ca2+ ingested via diet)
- Ca2+ excretion in urine is regulated by Ca2+ reabsorption: there’s no secretory pathway so if we want to increase calcium excretion, calcium reabsorption needs to decrease
- (the transcellular mechanisms for reabsorbing Ca2+ are the same throughout the renal tubule)
Ca2+ Reabsorption in the Proximal Tubule
- 20% of Ca2+ reabsorbed here gets into tubular epithelial cells via Ca2+ channels in the apical membrane
- would want to enter the cell b/c it is in such a LOW concentration inside - there’s a large driving force for Ca2+ to enter cells
- Ca2+ then exits via Ca2+ ATPase & Na+/Ca2+ Antiporter in the basoloateral membrane
- 80% of Ca2+ is reabsorbed here via the paracellular route b/c of solvent drag (b/c there’s extensive H2O reabsorption) & the lumenal positive transepithelial potential (created by Cl- reabsorption)
Ca2+ Reabsorption by the Thick Ascending Limb of the Loop of Henle
- 20% of filtered Ca2+ is reabsorbed by the thick ascending limb of the loop of Henle
- transcellular mechanisms for reabsorption are similar to those in the proximal tubule except here there is NO solvent drag b/c there is NO H2O reabsorption (it’s totally impermeable to water)
- paracellular reabsorption is driven only by the lumenal positive transepithelial potential (via ~electrophoresis)
Ca2+ Reabsorption by the Distal Tubule & CD
- 10% of filtered Ca2+ is reabsorbed by distal tubule & collecting duct via transcellular reabsorption ONLY using the apical Ca2+ channels & basolateral Na+/Ca2+ Antiporter + Ca2+ ATPase
- there is no paracellular transport b/c the transepithelial potential in the late DT/CD is luminal NEGATIVE, i.e. it wouldn’t drive cation uptake into the interstitium
Hormonal Regulation of Ca2+ Excretion
- Ca2+ comes in through the diet → enters a Ca2+ pool
- that pool is being handled by the Kidneys w/ Ca2+ excretion & in equilibrium w/ the bone
Calcitriol (1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3)
- the hormonally active form of Vit D w/ three hydroxyl groups
- it increases the level of calcium in the blood
Hypocalcemia (↓ plasma Ca2+)
1. → ↑ calcitriol secretion → ↑ Ca2+ reabsorption in gut & ↑ Ca2+ reabsorption by the distal tubule
- 2. → ↑ PTH secretion → ↑ bone resorption & ↑ Ca2+ reabsorption by loop of Henle & distal tubule
- effect is to elevate free Ca2+ in the Ca2+ pool
Hypercalcemia (↑ plasma Ca2+)
- → ↑ calcitonin secretion → ↑ bone formation
- more Ca2+ is locked into bone
PO43- Function & Distribution
• PO43- functions as a buffer, as part of nucleic acids, in formation of bone, etc.
• 86% of PO43- is locked in bone
• 14% is intracellular
• 0.03% is extracellular
• 90% of plasma PO43- is free & 10% is bound to proteins (& therefore cannot be filtered by the glomerulus)
PO43- Reabsorption Along the Renal Tubule
- 80% is reabsorbed in the proximal tubule
- 10% is the distal tubule & collecting duct
- leaving 10% to be excreted in the urine
How is phosphate reabsorbed in the proximal tubule?
- in the apical membrane of proximal tubule cells there is a Na+/ PO43- cotransporter that brings the 2 ions into the epithelial cells
- it couples PO43- uptake to the downhill movement of Na+ into cells
- PO43- crosses the basolateral membrane via PO43-/anion Antiporter
- the hormonal regulation of PO43- occurs by altering proximal tubule reabsorption
Low Plasma Phosphate (↓ plasma PO43-)
- → ↑ calcitriol secretion → ↑ PO43- absorption in the gut & ↑ PO43- reabsorption in kidney
- the same regulators of Ca2+ also regulate PO43-, however they’re not always doing so in the same direction
What is the effect of increased PTH in response to low levels of plasma calcium on phosphate levels?
- ↑ PTH → ↑ PO43- release from bone: it releases both Ca2+ & PO43- from the pool
- however it ALSO ↓ PO43- reabsorption (↑ PO43- excretion) in kidney
- therefore the 2 effects cancel each other out (unlike w/ Ca2+)
- PTH increases plasma Ca2+ levels but it DOESN’T increase PO43- levels significantly
What is the effect of increased calcitonin in response to high levels of plasma calcium on phosphate levels?
- ↑ calcitonin → ↑ PO43- incorporation into bone & ↓ PO43- reabsorption in the kidney, so more is excreted in the urine
- Calcitonin will overall decrease plasma phosphate levels
Different Transporters Handle Anionic & Cationic Substances/Drugs
- Endogenous Anions: Prostaglandins, Uric Acid
- Anionic Drugs: Penicillin, Salicylate, Ibuprofin, Adefovir (anti-HIV)
- Endogenous cations: Epinephrine, Norepinephrine
- Cationic Drugs: Morphine, Amiloride (K+ sparing diuretic), Verapamil (Ca2+ channel blocker), Vinblastine (anti-cancer drug)
- *unlike water & solutes being reabsorbed from the tubular lumen & transferred into the plasma, the anions & cations are being removed FROM the plasma & getting secreted into the renal tubule for excretion
Organic Anion Secretion in the Proximal Tubule
- organic anions are transported across the basolateral membrane from the blood into epithelial cells by an Antiporter
- as it pumps organic anions into the cell, α-KetoGlutarate is pumped out of the cell
- however the α-KG is recycled to drive this process; it gets pumped back into the cell via a Na+/α-KG Cotransporter
- α-KG is moving down its concentration gradient when it’s pumped out of the cell (used to get anion in), & up it’s concentration gradient when recycled back into the cell (Na+ provides the energy for this)
Once inside the tubular epithelial cells, how do organic anions get secreted across the apical membrane into the tubular lumen?
via a Cl-/Organic Anion Antiporter: Cl- is pumped into the cell while the Anion is dumped into the tubular fluid
Why during WWII when there was a shortage of penicillin was PAH (para-amino hippuric acid) added to penicillin stocks?
- because they are both organic anions, PAH would compete w/ penicillin for secretion into the proximal tubule via the basolateral organic anion/α-KG Antiporter
- if PAH was occupying some of these transporters, penicillin would stay in the blood stream longer (would have an increased half life) & while there fight bacterial infections
- the rate of penicillin secretion was decreased as a result of competition for transporters
Organic Cation (OC+) Secretion in the Proximal Tubule
- a passive basolateral organic cation transporter allows entry of OC+ into the tubular epithelial cells
- once in the cell, 2 different transporters handle the OC+
- 1. Cation/H+ Antiporter
- 2. MDR-related transporters: ATP driven, multi-drug resistance transporter
What can competition between cationic drugs (such as morphine & amiloride) result in?
How are proteins that accidentally make it through the glomerular capillary membrane & are filtered reabsorbed back into the plasma?
- via receptor-mediated endocytosis in the proximal tubule
- the proteins that do escape tend to be small positively charged ones
- the scavenging system in the proximal tubule involved in taking up those peptides use megalin & cubulin receptors in the apical membranes of tubular endothelial cells
- these receptors are non-specific peptide/protein binding receptors that will ‘grab onto’ proteins in the tubular lumen & endocytose them
- the proteins are absorbed into clatharin coated vesicles in the cytoplasm
- eventually they are transmitted to lysosomes which degrade them into AAs while the receptors are recycled back to the apical membrane surface
What do defect in the megalin or cubulin receptors or V-ATPases in Proximal Tubule cells cause?
Fanconi’s syndrome - characterized by the appearance of protein in urine (proteinuria)
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