Tubular Functions Flashcards
Na+ Reabsorption
Proximal tubule- site of reabsorption of bulk of filtered Na, Cl and H2O
Thick ascending limb- further absorbs 25% of filtered load
Distal Convoluted tubule- 5%
Collecting duct- 3%
Nephron Segments
Convoluted and Straight Proximal tubule
Reabsorb:
- NaCl & H2O
- K+
- HCO3-
- phosphate
- Ca2+
- glucose & aa
- peptides & protein
- mono, di & tricarboxylates
- urea
Secrete:
- H+
- NH3
- organic cations & anions
Bulk reabsorption & acidification
Reabsorption in PT is isotonic
Proximal tubule []/ Plasma [] or TF/P ratio
Start @ Bowman’s 0% to end 100%
- ratio for inulin increases all the way; water is reabsorbed along entire PT
- TF/P ratio for osmolality & Na changes hardly at all. Reabsorption at PT= isotonic
- gluc and aa [] fall rapidly @ beginning of tubule (90% of filtered load absorbed w/in 1st 25%); End >99% of solutes absorbed
- [] of Cl- increases initially & increases more slowly later.
- Bicarb [] falls in early & contiues to fall for remainder of tubule.
- The transepith potential diff changes; -3 mV to +2 mV later.
- The early negative mV= electrogenic reabsorption of gluc & aa
- late prox tubulue, Cl- [] increased above that in plasma, diffusion of Cl- ions through paracell pathway, generates + lumen potential which causes passive Na reabsorption
Early Phase in PCT
Early phase of reabsorption by proximal tubule, electrogenic Na dependent absorption of organic solutes like gluc, aa, mono & dicarboxylates & phosphate generate - lumen potential diff
Organic solutes exist cell through facilitated diffusional transporters!
- potential diff is driving F of paracell Cl- reabsorption
- Na reabsorbed through exchange for protons.
- H+ liberated w/in cell cause generation of intracell bicarb which exits across BASOLATERAL mem by Na dep co transport
- Na dep absorption generates osmotic driving F w/in lateral intercellular spaces for H2O absorption (through aquaporins & paracell)
- Solute & H2O uptake into peritubular caps depends on Starling F!
- H2O movement through paracell path entrains some solute move in “solvent drag” which allows reabsorption of some cations!
Reabsorptive Step Summary
- Na+/K+pump sets up favorable electrochem gradient for Na+ entry
- Ion transport creates voltage gradient lument to interstitium :
- lumen negative (early)- electrogenic Na+ organics, NaHCO3- reabsorption (Cl- reabsorption so [Cl-] increasess)
- lumen positive (late)- diffusion of Cl- ions from lumen to blood- drives passive Na+ reabsorption
- H2O follows solutes by osmosis
- Some solutes reabsorbed along with water flow (solvent drag)- proximal tubule very leaky epith
- reabsorption of H2O concentrates solutes (Cl-, urea) in lumen: passive reabsorption down []
Late Phase- Cl-/ anion recycling
Last half of prox tubule, Na & Cl reabsorption occurs via both trans & paracell routes
- Na & Cl enter cell through // arrangement of a Na/H exhanger & Cl/base exchanger
- intracell anions such as oxalate & formate exhnage for Cl-, then are protonated in acid pH of lumen & reenter cell through non ionic diffusion
- [] of Cl- increased in early part NOW Cl- diffuses down its gradient through paracell pathway
- diffusion of Cl- generates lumen + potential. Potential diff drives passive reabsorption on Na & other cations
- H2O moves through paracell path causes reabsorption of cations by solvent drag
Proximal Urea reabsorption- passive
As Na- coupled solute & H2O transport proceeds in proximal tubule, [] of urea rises.
This increas in luminal [] provides driving F for transcell reabsorption of urea by facilitated diffusion & paracell reabsorption of simple diffusion.
Reabsorption of H2O further aids urea reabsorption by solvent drag.
Glucose
Na Dep cotransport
Early prox tubule: high capacity, low affinity transporter SGLT2
Late proximal tubule: low capacity, high affinity transporter SGLT1; scavenger f
Tm limitation= increased plasma levels> threshold= loss in urine
loss of transporters= increased urinary loss
AA
generally Na dep cotransport (broad)
Normally 0 gluc or aa escape PCT
BUT Tm limitation to reabsorption
Glycosuria in diabetes mellitus
Phosphate reabsorbed in PT
Proximal tubule reabsorbs 80% of filtered phosphate & distal tubule reabsorps remainder.
Excrete 10% of filtered load
- reabsorption of Pi by proximal tubule is trancell via NaPi cotransporter
- cell mech of Pi reabsoprtion by distal tubule is ?
- normal range of plasma phosphate is such that given the Tm, small changes in plasma phosphate cause large changes in excretion
- inhibited by PTH
Ca reabsorbed mostly in PT & TAL (paracell & transcell)
65-70% of proximal tubule
29-34% Rest in loop of Henle & distal tubule
less than 1% reabsorbed by collecting duct
200 mg/d excreted in urine
Reabsorption of Ca2+ in PT & TAL occurs via paracell & transcell
Ca2+ reabsorption via paracell path is qualitatively more important!
For transcell reabsorption, Ca diffuses down its electrochem gradient across apical mem through channels & into cell.
At basolateral mem, Ca2+ extruded from cell against its electrochem gradient by Ca ATPase & Na/Ca exchanger
Reg via PTH= increase reabsorption in DCT
Proteins & Peptides
PT reabsorbes around 99% of oligopeptides filtered.
Few peptidases @ brush border of PT cells.
Brush border enz hydrolyze enz & release free aa & oligopeptides.
Free aa are absorbed by cotransport.
Oligopept resistant to brush border enz & reabsorbed through apical H/oligopep PepT1 & T2.
glomerular filtration barrier prevents protein but albumin [] is low!
Also lysozyme &ANP & insulin= absorbed by R mediated endocytsosis
Organic anions & cations
Late PT secretes wide range of both endogenous & exogenous organic cations & anions.
Organic cation & anion transporters are responsible for basolaterla uptake & apical secretion mech.
Transporters are broad so competition for transport exists
- creatinine w/ other OC or PAH with other OA
- alter plasma levels
Acid Base Balance
- Reabsorption of filtered HCO3-
- elimination of non volatitle acids
- formation & excretion of NH4+
Reabsorb filtered bicarb & secrete excess acid by secreting ammonia & titratable acid formation.
PT reabsorbs mots of bicarb!
Bicarb reabsorption
H+ secretion across apical mem of cell occurs via Na/H exhanger & H-ATPase.
Exchanger uses 2nd active transport
W/in cell, H+ & HCO3- produced from carbonic acid through rxn catalyzed by CA
H+ secreted into tubular fluid, whereas bicarb exits across basolateral mem & returns to peritubular blood.
Majority of HCO3- exits through Na dep cotransporter.
In lumen, carbonic andhydrase CA also present in brush border fo PT cells. Enz catalyzes dehydration of carbonic acid in luminal fluid.
Formation of Titratable Acid
Reabsorption of filtered bicarb buffers some of acid produced by body, there is great excess of H+ production remaining.
Acid export transporters (Na/H exhnage & H+ pump) have limit!
- pH to which tubular fluid can fall to excrete daily acid production
- buffer secreted protons against filtered HPO42- (pK around 6.8)
- H+ accepted & forms H2PO4
- This is the other 30-20% which PT cannot reabsorb!
Excretion of H+ by forming NH4+
2nd mech for excretion of acid is by syn of NH3 gas from glutamine
- inside cell, some NH3 combines w/ H+ to form NH4+ which exits cell in exchange for Na+
- some NH3 leaves cell by passive diffusion across apical PM & combines w/ secreted H+ in tubule lumen to form NH4+ which is excreted in urine
- alpha ketoglutarate metabolized to glucose & CO2 & H2O- then to carbonic acid & to H+ & HCO3-
- HCO3- absorbed w/ Na+
- like buffering H+ w/ phosphate, excretion of buffer is matched by “new “ bicarb syn by kidney
Nephron Segments
End of prox straight tubule, change to thin descending Henle= extensive brush border of PT lost & cells don’t have many mitchondria!
Thin limbs passively transport solutes & H2O
Turns to ascending Henle loop, which head towards cortex.
Cells are very similar in both limbs!
Descending limb= hypertonic due to H2O moving out of tubule
Ascending limb= hypotonic, Dilution of active salt reabsorption in thick ascending limb.
Reabsorb: NaCl, HCO3-, Mg2+
Thick Ascending LImb
in thick ascend limb, sodium absorption via transcell & paracell.
Na enters through electroneutral cotransport w/ Cl- & K+.
Na+ enters cell by Na/H exhanges- driveing 10% of bicarb reabsorption.
- Triporter NKCC2 inhibted by loop diuretics & couple movement of 1 Na+ to 1 K+ & 2 Cl- into cell down []
- Cl- exits across basolateral mem
- large K+ amt enters through NKCC2 recycles into lumen by secretion
Replenish luminal K+ supply:
- K+ secretion also produces lumen + potential diff
- transepith potential provides a driving F for diffusion of cations through paracell
- paracell path accounts for around 1/2 total Na+ reabsorption by thick limb!
ascending limb of Henle- charac by low H2O perm! Removing NaCl from luminal fluid reduces osmotic P& becomes hypotonic to plasma! “diluting segment”
DCT
reabsorb 5% NaCl
6% HCO3-
Secrete: K+, H+
Hypotonic sol’n!
Cells of thick ascending limb & DCT are simiar! Cells of macula densa mark the transition
Salt & H2O reabsorb in distal nephron:
- reabsorb of salt leads to dilution of tubular fluid & DCT delivers hypotonic fluid to collecting duct
Cell Types
Principal cells- Na reabsorb, K secrete
Intercalated cells- H+ secrete & HCO3- reabsorb
Early Distal Tubule Transport
Na reabsorption in DCT transcell!
Apical step of Na uptake mediated by electroneutral Na/Cl transporter
Exit of Cl- via channel
However, NCC differs from NKCC2 in being indep of K+ & very sensitive to thiazide diuretics!
Collecting Duct
Reabsorb: NaCl, K+, HCO3-, Urea
Secrete: K+, H+
Both in cortex & medulla
- CD deals w/ smalles fractions of fitlered load of electrolytes; have principal cells (Na absorb, K secrete) & intercalated cells (H+ secretion, HCO3- reabsorption)
Aldosterone regulates Na/K actions by stimulating Na reabsorb & K secrete & H secrete.
ADH acts on PCs to increase perm to H2O urea.
Response to ADH indep of Na & allows collecting duct to excrete H2O load or to conserve H2O
ANP antagonises effects of aldosterone & ADH to lose salt & H2O
Principal Cell
Na reabsorption by PC is dep on channels. K+ secretion by Pcs also occurs through channels
- Na crosses apical mem through ENaC (channel)
- ENaC inhibited by amiloride
- Na entry across luminal mem depol luminal mem potential diff & hyperpol transeptih potential
- direct electrochem coupling of Na absorb & K secrete
- Principal cells absorb H2O by ADH
- inner & outer medullary collecting ducts reabsorb only 3% of Na
Aldosterone
Aldosterone acts on principal cells by binding to MRs & regulating gene transcription.
Early ENaC effects involve increase in channel number & apical Na+ perm! Target newly syn Na-K pumps to basolaterla mem
MRs & Grs. distinguish poorly b/t glucocorticoids & mineralocorticoids.
Plasma [] of glucocorticoids >> aldosterone; expect Na retention by glucocorticoids but doesn’t happen!
The enz protects MR specificiyt by protecting them from activation by cortisol (glucocorticoid)
11 B hydroxysteroid dehydrogenase 2 co localizes w/ intracell adrenal steroid R, irreversibly convets cortisol into cortisone (inactive) Doesn’t metabolize aldosterone.
A def in enzyme may mimc mineralocorticoid excess!
Carbenoxolone- inhibits enz, prevents cortisol metabolism & abnormal activation of MRs by glucocorticoid.
Glycerrhetinic acid, another inhibitor, natural licorice. Excess can cause abnormal Na retention & hyperT!
Intercalated Cells
IC cells responsible for H+ secrete & K+ resorption
Electrogenic H+ pump is vacuolar type ATPase.
Establish steep traneptih H+ [] gradients, lower urine to pH of 4-5
Pumps expressed in IC cells of corticol collecting tubule & in inner & outer medullary collecting duct
Reg of apical H+ pump:
- transepith electrical potential modulates H+ pump rate. Aldosterone increase Na+ uptake in apical part by principal cells in CCT; negative lumen potential increase to stimulate H+ pump
- Aldosterone increases syn of H+ pumps indep of voltage changes
Absoroption of K+ through H/K pump ATP
In K+ depletion, expression of H/K pump increase dramaticaly & associated w/ higher H+ secretion & hypokalemic alkalosis
Hyperaldosteronism
Coupling b/t collecting duct transport of Na, K & protons which reg by aldosterone explains effects of mineralocorticoid excess
Na retention
- hyperT
- hypervolemia
- edema
Hypokalemia
- m. weakness
- constipation
- changes in EKG
Alkalosis
- tetany, cramps
K balance
Homeostasis govered by K+ balance & distribution.
Dietary intake 80-120 mmol/day; more than entire ECF!
For plasma K+ cotent to remain constant, body excrete K+
Kidney mostly excretes K+
Most of K+ inside cells (skeletal m.)
Of total intracell K+ content, shuttling1% to/from ECF can cause 50% in extracell K+ !
K+ balance 2
Skeletal m. are buffer for minimizing short term ECF K+ changes
80% of ingested K+ load temp onto m. cell so plasma [] rises only a little.
Transfer of excess K+ into cells- rapid & complete w/in 1 hr!
W/ delay- kidney excrete excess K+
K uptake into cells
Insulin, epi via B adrenergic R, promote transfer of K+ from extracell to intracell through Na/K pump
Cell K+/H+ Exchange
Acid base disturbances- affect K+ distribution b/c cell handling of K+ & H+ are linked.
Acidemia leads to hyperkalemia as tissues release K+
Alkalemia leads to hypokalemia
Extracell acidosis increas in intracell [H+} which competes w/ K+ for binding intracell anions.
Displaces K+ which then leaves the cell.
Intracell acidosis inhibits both NaK pump & Na/K/Cl cotransporter both of which move K+ into cells.
K+ in nephron
Kidney filters K+ & reabsorbs it along PT 80% & loop of henley 10% & 10% enter DCT! Medullary collecting duct reabsorbs K+
On normal/high K+ diet; kidney net secretor of K+
When external K+ balance demands that kindeys excrete K+, the collecting tubule & medullary collecting duct secrete K+ into tubule lumen.
Secretion accounts for most of urinary excretion of K+
On low K+ diet:
distal tubule & CCT switch to reabsorb K+ only 1-3% in urine
Switch= up reg H/K exchanger
K+ Secretion Reg
Rate of fluid flow increases so does K+ secretion
Extracell vol expands, osmotic diuresis, admin diuretics leads to enhanced K+ excretion.
Increased urine flow associated with increase Na+ excetion
Increased luminal flow increase Na+ delivery to tubules, raising lumen [Na+] & uptake from ENaC, depol apical mem , favoring K+ exit to lumen!
Fall in Na+ uptake hyperpol apical mem- inhibiting K+ secretion.
Amiloride ENaC blocker)= K+ sparing diuretic!
Both mineralocorticoid & glucocorticoids cause kaliuresis, 1 hyperaldosteronism. K+ wasting & hypokalemia!
Adrenocorticol def= K+ retention, hyperkalemia.
Aldosterone- induces K+ secretion by increasing transcription of genes that enhance Na+ reabsorption & directly increasing K+ activity in channels in apical mem.
Glucorticoids enhance K+ excretion by increasing flow along K+ secretory sys via GFR increase.
Glucocorticodis have no K+ transport effect unelss high [] or 11 B hydroxysteroid dehydrogenase is I!
Acid-base disturbances; alkalosis leads to increased K+ excretion
acidosis- reduces K+ excretion.
Channel activity increased by increasing pH & vice versa!
K+ Balance
