DISTAL TUBULAR DISTAL TUBULAR FUNCTION FUNCTION Prof Harbindar Jeet Singh Faculty of Medicine Universiti Teknologi MARA
DISTAL TUBULAR DISTAL TUBULAR FUNCTIONFUNCTION
Prof Harbindar Jeet SinghFaculty of Medicine
Universiti Teknologi MARA
Objectives of this lecture
Distal tubular handling of NaCl
Calcium and magnesium
Potassium
Phosphate
The distal tubule is composed of three morphologically distinct segments
1. Thick ascending limb of the loop of Henle (pars recta)
2. Macula densa
3. Distal convoluted tubule (pars convoluta)
The thick ascending limb can be divided into
i) a medullary segment
i) a cortical segment
The thick ascending limb is involved in the transport of NaClfrom the lumen to the surrounding interstitium
Its epithelium is impermeable to water
The reabsorption of NaCl is mediated by an Na+-K+-2Cl-
cotransport mechanism
It reabsorbs about 30 % of the NaCl filtered at the glomerulus
Transport of NaCl in the TAL
Na+ exits the cell at the basolateral membrane via the Na+-K+-ATPase, Cl- exits via the K+/Cl- co-transporter
The energy for this reabsorptive process is provided by theNa+-K+-ATPase that is located in the basolateral plasma
Vasopressin (ADH) strongly upregulates this co-transporter in the thick ascending limb
This can be inhibited by loop diuretics like furosemide and bumetanide
Calcium handling by the TALH
About 15-20% of the filtered load of Ca 2+ is reabsorbed in the TAL
About half of calcium reabsorption in TALH is passive and the other halfis active.
The passive transport is via the paracellular route, driven by the positive lumen PD created by the active reabsorption of NaCl and the luminal membrane recycling of K+.
The active component is transcellular.Calcium enters via ECaC passively andthen extruded actively either through Ca pump or Na+/Ca 2+ exchange andactive sodium extrusion
PTH increases Ca 2+reabsorption in the TALH.
It increases the paracellular permeabilityto calcium via an effect on claudin-16,and perhaps also the some activecomponent of calcium transport.
The TAL is the major site for magnesium reabsorption, accounting for 60-70% of magnesium reabsorption
Like calcium, the mechanism of reabsorption of Mg 2+in the TALH is paracellular and passive, involving a specific tight junction protein called paracellin-1/Claudin-16. The driving force for paracellular magnesium reabsorption is the positive lumen PD
Loop diuretics, like furosemide, which inhibit the Na+-K+-2Cl-co-transporter, and prevent the establishment of the lumen positive PD inhibit Ca 2+ and Mg 2+ reabsorption
Magnesium handling by the TALH
Lumen PTH enhances the reabsorption ofMg 2+ by increasing NaCl reabsorption generating a trans-epithelial PD, and increasingthe passive permeability of TALHto paracellular transport
Potassium handling in the TAL
The medullary TAL, which has a high basolateral-to-apical K+ permeability ratio exhibits net K+ reabsorption
The corticol TAL, which has a low basolateral-to-apical K+ permeability ratio exhibits net K+ secretion
There is net K+ reabsorption in the TAL, where about 25% of the filtered load is reabsorbed.
Reabsorption is both passive via paracellular route because of lumen-positive voltage, and transcellular route involving secondary
active Na+-K+-Cl cotransport (NKCC2).
Inhibited by loop diuretics like furosemide
Tubular function (Distal Convoluted tubule - DCT)
The DCT begins beyond the macula densa and extends to the collecting duct
Reabsorption of NaCl is present in the DCT mainly via the transcellular routeinvolving the thiazide sensitive Na+/Cl cotransporter and the basolateral Na+-K+-ATPase.
The Na+/Cl- co-transporter is up-regulated by aldosterone.
In the CCT Na+ reabsorption is mainly transcellular and mediated by the principal cell.
About 5% of the filtered load is handled at the DCT and CCT.
Sodium crosses the apical membrane of the principal cell via the ENaC, which is blocked by amiloride.
The medullary CT only reabsorbs about 3 % of the filtered load.
The late distal tubule (CNT) together with the initial collecting tubule (ICT)has the greatest capacity for K+ secretion
K+ secretion is sodium chloride dependent, and is inhibited by thiazide diuretics
The secretion of potassium is a two-stage process
a) Uptake by the cell from the interstitium by Na+-K+-ATPase at the basolateralsurface
b) Passive diffusion of potassium from the cell to the tubular lumen
The luminal or apical membrane of the principal cells is highly permeable to K+
In cases of potassium depletion, there is net reabsorption of K+ in the late distal tubule. It occurs through the α intercalated cells.
The ICT and the CCT have approximately 70% principal cells (which secrete K+) and30% intercalated cells (some of which reabsorb K+)
The capacity for K+ secretion diminishes in the MCD. If anything there might be some K+ reabsorption in the MCD
Mechanism of potassium secretion in the distal tubule
a) Uptake by the cell from the interstitium by Na+-K+-ATPase
b) Passive diffusion ofpotassium from the cell to the tubular lumen
Renal tubular handling of potassium
A number of factors influence distal tubule K+ secretion
ii) NaCl delivery to the distal tubule
Increase NaCl delivery increases K+ secretion and reduced delivery decreases K+ secretion by the distal tubule
iii) Effect of distal tubular flow rate increases K+ secretion
For a given increment in flow, distal secretion is greater when K+ is high then when it is moderate
When K+ intake is low, flow has little effect on secretion
i) Increased ECF K+ conc
a) by stimulation of Na+-K+-ATPaseb) increased aldosterone secretion
As might occur in increased ECFV or diuretic use
Potassium excretion as a function of plasma concentration
Intake
K+ secretion as function of distal tubular flow
Diet
iv) Aldosterone
Aldosterone stimulates active reabsorption of Na+ by the principal cells, which is mediated through Na+-K+-ATPaseat the basolateral surface
Aldosterone increases the permeability of the luminal membrane for potassium
v) Acute acidosis decreases potassium secretion, whereas alkalosis increase potassium secretion
Chronic acidosis leads to an increase in K+ secretion
Acidification leads to complete cessation of channel activity. conductance of both K+ and Na+ decreases
vi) Role of anions in potassium secretion
Infusion of sodium bicarbonate stimulates K+ excretion
K+ secretion rises sharply in the presence of poorly permeableanions such as sulphate
vii) Effect of diuretics
Diuretics affect K+ excretion in several ways
a) Directly acting on the transport mechanism
e.g. carbonic anhydrase inhibitors stimulate secretion in the distal tubule
b) Kaliopenic diuretics such as , spironolactone, amiloride, triamterene inhibit K+ secretion
vii) Circadian fluctuations
K+ excretion by the kidney is lowest in the early morning (5-6 am) and rises to peak in the late afternoon (4-6 pm)
This diurnal rhythm is independent of food intake or activity.
c) Furosemide and loop diuretics are powerful inhibitors of Na+/K+/2Cl- co-transport mechanism in the TAL.
This collapses the positive luminal PD difference therebyincreasing potassium leakage.
The increased flow to the distal region also further contributes to the increased secretion
viii) Other hormones
a) Vasopressin
Vasopressin stimulates Na+ reabsorption and K+ secretion in the distal tubule
The rise in Na+ reabsorption is triggered by activation of basolateral V2 receptors, which increase apical membrane Na+ conductance that is dependent on cAMP and PKA.
Concomittant depolarisation of the apical membrane stimulates K+ secretion
Vasopressin also increases the activity of the low-conductance K+ channels in the apical membrane
b) Insulin
Insulin reduces K+ excretion by the kidney independently of changes in plasma K+ conc and aldosterone
It is possible that this action is associated with a reduction in Na+ reabsorption secondary to the inhibition of apical sodium channels by insulin
c) Glucocorticoids
Glucocorticoids stimulate K+ excretion by increased flow and distal sodium delivery
Calcium and magnesium handling by the distal tubule
Approximately 10-15% of filtered calcium is reabsorbed in the distal tubule
As the PD is lumen negative and the calcium concentration is below that of plasma, Ca 2+ absorption is therefore active in this segment
The DCT is the primary site for PTH action, stimulating Ca 2+ reabsorption via c’AMP
Calcium enters apically through ECaC, diffuses across the cytosol bound to calbindin-D28K and exits basolaterally through a calcium pump, or a sodium-calcium exchanger
The distal convoluted reabsorbs about 5-10% of the filtered load of magnesium.
Phosphate reabsorption
Approximately 10% of the filtered load of phosphate might be reabsorbed in the DCT and the CCT.
This might only be evident during instances of phosphate deficiency.
THANK YOU
Potassium transport along the nephron