TUBULAR TUBULAR REABSORPTION OF REABSORPTION OF GLUCOSE, AMINO GLUCOSE, AMINO

ACIDS, UREA & OTHER ACIDS, UREA & OTHER ELECTROLYTESELECTROLYTES

LECTURE 6LECTURE 6

Glucose reabsorption general Glucose reabsorption general consideration consideration

• Glucose reabsorption is calculated as the Glucose reabsorption is calculated as the difference between the amount of glucose difference between the amount of glucose filtered by the kidney and the amount filtered by the kidney and the amount excreted.excreted.

• When plasma glucose (PWhen plasma glucose (PGG) is increased to ) is increased to

near 200 mg/dl, glucose begins to appear near 200 mg/dl, glucose begins to appear in the urine – this is called the “glucose in the urine – this is called the “glucose renal threshold”renal threshold”

• As glucose is further increased, more As glucose is further increased, more glucose appears in the urine.glucose appears in the urine.

• At very high filtered glucose, reabsorption At very high filtered glucose, reabsorption remains constant, this is called “tubular remains constant, this is called “tubular transport maximum” for glucose (Tmtransport maximum” for glucose (TmGG))

– At this maximum transport, all the glucose At this maximum transport, all the glucose carriers are saturated and no more glucose carriers are saturated and no more glucose can be transportedcan be transported

Glucose reabsorptionGlucose reabsorption

• Mechanism of glucose reabsorptionMechanism of glucose reabsorption

• Secondary active transportSecondary active transport

• Luminal membraneLuminal membrane– Cotransport with NaCotransport with Na

• Basolateral membraneBasolateral membrane– GLUT2GLUT2

Cellular Mechanism for Cellular Mechanism for Glucose ReabsorptionGlucose Reabsorption

The luminal membrane of the epithelial The luminal membrane of the epithelial cells faces the tubular fluid (lumen) and cells faces the tubular fluid (lumen) and contains the Nacontains the Na++-glucose co-transporter. -glucose co-transporter. The peritubular membrane or basolateral The peritubular membrane or basolateral membrane of the cells faces the membrane of the cells faces the peritubular capillary blood and contains peritubular capillary blood and contains the Nathe Na++-K-K++ ATPase and the facilitated ATPase and the facilitated glucose transporter.glucose transporter.

Cell of the proximal tubuleCell of the proximal tubuleLUMENLUMEN BLOODBLOOD

NaNa++

GlucoseGlucose

NaNa++

GlucoseGlucose

KK++

Cellular Mechanism for Glucose ReabsorptionCellular Mechanism for Glucose Reabsorption

Steps involved in reabsorbing glucose from Steps involved in reabsorbing glucose from tubular fluid into peritubular capillary bloodtubular fluid into peritubular capillary blood

1)1) Glucose move from tubular fluid Glucose move from tubular fluid cell by binding cell by binding with Nawith Na++ to the cotransport protein (GLUT1) which to the cotransport protein (GLUT1) which rotates in the membrane rotates in the membrane Na Na++ and glucose released and glucose released to ICF. Glucose is transported against an to ICF. Glucose is transported against an electrochemical gradient.electrochemical gradient.

2)2) NaNa++ gradient is maintained by the Na-K ATPase in the gradient is maintained by the Na-K ATPase in the peritubular membrane. Because ATP is used directly peritubular membrane. Because ATP is used directly to energize the Na-K ATPase and indirectly to to energize the Na-K ATPase and indirectly to maintain the Na gradient, Namaintain the Na gradient, Na++-glucose cotransport -glucose cotransport called secondary active transport.called secondary active transport.

3)3) Glucose transported from cell Glucose transported from cell peritubular capillary peritubular capillary blood by facilitated diffusion (GLUT2). Glucose move blood by facilitated diffusion (GLUT2). Glucose move down electrochemical gradient, no energy required.down electrochemical gradient, no energy required.

TUBULARTUBULARLUMENLUMEN

INTERSTITIALINTERSTITIALFLUIDFLUID

GLUT 2GLUT 2 SGLT 2SGLT 2

NaNa++

KK++

GlucoseGlucose GlucoseGlucoseOne NaOne Na++

Early proximalEarly proximaltubule celltubule cell

GLUT 1GLUT 1 SGLT 1SGLT 1

NaNa++

KK++

GlucoseGlucose GlucoseGlucoseTwo NaTwo Na++

Late proximalLate proximaltubule celltubule cell

Glucose ReabsorptionGlucose Reabsorption

Glucose Titration Curve and TGlucose Titration Curve and Tmm

A glucose titration curve depicts the A glucose titration curve depicts the relationship between plasma glucose relationship between plasma glucose concentration and glucose reabsorption. concentration and glucose reabsorption. It is best understood by examing each It is best understood by examing each relationship separately and then by relationship separately and then by considering all three relationships considering all three relationships together.together.

InulinInulin

GlucoseGlucose

PP

UV

UV

Plasma glucose (PPlasma glucose (PGG))

Glu

cose

rea

bso

rbed

(T

Glu

cose

rea

bso

rbed

(T

GG))

TmTmGG

SplaySplay

““Ideal”Ideal”ActualActual

GlucoseGlucoseTitrationTitration

CurveCurve

Renal threshold =Renal threshold =300 mg/dl300 mg/dl

375 mg/min (Tm375 mg/min (TmGG) divided by ) divided by

125 ml/min (GFR)125 ml/min (GFR)

Actual renal threshold =Actual renal threshold =200 mg/dl200 mg/dl

• Tubular maximum (Tmg) Tubular maximum (Tmg) – Maximum absorptive capacity for glucose Maximum absorptive capacity for glucose

by renal tubular cellsby renal tubular cells– 375 mg/min (female 300mg/min)375 mg/min (female 300mg/min)

• Renal thresholdRenal threshold– Plasma glucose level at which glucose Plasma glucose level at which glucose

first appear in urinefirst appear in urine– 200mg/dl in arterial; 180 mg/dl in venous200mg/dl in arterial; 180 mg/dl in venous

• Glucose absorption is inhibited by Glucose absorption is inhibited by Phlorhizin Phlorhizin competes for binding to competes for binding to the carrierthe carrier

blood glucose level (blood glucose level ( renal threshold) renal threshold) exceed Tm exceed Tm glucose in urine glucose in urine glucosuria Diabetes Mellitusglucosuria Diabetes Mellitus

800800

600600

400400

200200

000 200 400 600 8000 200 400 600 800

Plasma glucose (mg/dl)Plasma glucose (mg/dl)

Glu

cose

filt

ered

, rea

bso

rbed

, G

luco

se f

ilter

ed, r

eab

sorb

ed,

or

excr

eted

(m

g/m

in)

or

excr

eted

(m

g/m

in)

Threshold (200)Threshold (200)

SplaySplay

ExcretedExcretedUUG G x Vx V

TmTmGG (375) (375)

ReabsorbedReabsorbed

FilteredFilteredGFR x PGFR x PGG

The threshold for glucose is affected by the The threshold for glucose is affected by the following:following:

• GFR – a low GFR causes an increased threshold GFR – a low GFR causes an increased threshold because the filtered glucose is decreased and the because the filtered glucose is decreased and the kidney can reabsorb the filtered glucose even kidney can reabsorb the filtered glucose even though the plasma glucose is increased (more though the plasma glucose is increased (more time for reabsorption)time for reabsorption)

• TmTmGG – a decreased Tm – a decreased TmGG lowers the threshold lowers the threshold

because the tubules have a reduced capacity to because the tubules have a reduced capacity to reabsorb glucose.reabsorb glucose.

• Splay – “rounded” as it approaches its maximum Splay – “rounded” as it approaches its maximum which is caused by different nephrons having which is caused by different nephrons having different reabsorption and filtering capacities.different reabsorption and filtering capacities.

Amino acid reabsorptionAmino acid reabsorption

• All filtered AAs are reabsorbed in PCTAll filtered AAs are reabsorbed in PCT

• Luminal membraneLuminal membrane– Cotransport with NaCotransport with Na

• Basolateral membraneBasolateral membrane– diffusiondiffusion

Bicarbonate reabsorptionBicarbonate reabsorption

• 90% of filtered is reabsorbed in PCT90% of filtered is reabsorbed in PCT

• Filtered HCOFiltered HCO33 + H + H22O O HH22COCO33

• HH22COCO33 H H22O + COO + CO22 in the presence of in the presence of

carbonic anhydrasecarbonic anhydrase

• COCO22 diffuses into the cell + H diffuses into the cell + H22OOHH22COCO33

• HH22CO3 CO3 CA CA H + HCO H + HCO33

• HCOHCO33 is reabsorped is reabsorped

• HH++ is secreted in exchange for Na is secreted in exchange for Na ++

Bicarbonate reabsorptionBicarbonate reabsorption cont. cont.

LumenLumen Tubular cellTubular cell BloodBlood

NaNa++

FiltrateFiltrate NaNa++

HCOHCO33

++ H+H+ HH22COCO33

HH22O + COO + CO22

HH22COCO33

CACACOCO22 + H + H22OO

HH++ HCOHCO33

Tight junctionTight junction

Brush borderBrush border

Phosphate reabsorptionPhosphate reabsorption

• Bones, teeth & skeleton (80%)Bones, teeth & skeleton (80%)• Intracellular P (20%)Intracellular P (20%)• Plasma P 1mmol/l freely filteredPlasma P 1mmol/l freely filtered• 1/3 of filtered is excreted in urine1/3 of filtered is excreted in urine• Cotransported with NaCotransported with Na• Rate of absorption is under the control of Rate of absorption is under the control of

PTH & VD (PTH & VD (rate of absorption)rate of absorption)• Compete with glucose: blocking glucose Compete with glucose: blocking glucose

P reabsorptionP reabsorption

Urea reabsorptionUrea reabsorption

• Plasma urea concentraion 15-40mg/100mlPlasma urea concentraion 15-40mg/100ml• End product of protein metabolismEnd product of protein metabolism• 40-50% of filtered urea reabsorbed40-50% of filtered urea reabsorbed

– Passive diffusionPassive diffusion– Reabsorbed in consequent of Na reabsorption Reabsorbed in consequent of Na reabsorption

• 50-60% excreted50-60% excreted– GFRGFR– Concentration in bloodConcentration in blood

Urea reabsorption Urea reabsorption cont.cont.

GFR (renal disease; low renal blood GFR (renal disease; low renal blood flow) flow) urea concentraion in plasmaurea concentraion in plasma

GFRGFR urea filtered urea filtered GFRGFR slow flow rate of filterate slow flow rate of filterate more more

urea is absorbed to bloodurea is absorbed to blood

InulinInulin

ClCl

KK++ NaNa++

osmosm

HCOHCO33

AminoAminoacidsacids

GlucoseGlucose

2.62.6

2.42.4

2.22.2

2.02.0

1.81.8

1.61.6

1.41.4

1.21.2

1.01.0

0.80.8

0.60.6

0.40.4

0.20.2

0 25 30 75 1000 25 30 75 100

% Proximal tubule length% Proximal tubule length

TF

TF PP

Tubular secretionTubular secretion

• From peritubular blood From peritubular blood interstitium interstitium tubular cell tubular cell tubular lumen tubular lumen

• Secretion:Secretion:– Passive NH3, salicylic acidPassive NH3, salicylic acid– ActiveActive

• Tm: creatinine; PAHTm: creatinine; PAH• No Tm: K; HNo Tm: K; H

Tubular secretion Tubular secretion cont.cont.

• PotassiumPotassium– 90% of filtered K is reabsorbed (PCT)90% of filtered K is reabsorbed (PCT)– K secreted DCT In exchange for Na; under K secreted DCT In exchange for Na; under

the control of Aldosteronethe control of Aldosterone

• HydrogenHydrogen– Excretion is inversely proportional to K Excretion is inversely proportional to K