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PROXIMAL TUBULAR

FUNCTION
Professor Harbindar Jeet Singh
Faculty of Medicine
Universiti Teknologi Malaysia
Objectives of the lecture

1. Characteristics of the proximal tubule


2. Proximal tubular function

Proximal tubular handling of


NaCl,
Water,
Glucose,
Calcium and magnesium,
Potassium,
Phosphate
Ultrafiltration takes place in the glomerulus

Reabsorption and secretion in the kidney takes place in the

proximal tubule,

loop,

distal tubule and

the collecting duct


The proximal tubule is often divided into:

Histological Ultrastructural

Proximal tubule - Pars convoluta (PCT) S1-segment


(convoluted part)
S2-segment
- Proximal straight
tubule (PST) S3-segment
(straight part)
The main function of the proximal tubule is the isosmotic
reabsorption of about 60-65% of the glomerular filtrate
Proximal tubular reabsorption therefore plays a crucial role
in the maintenance of fluid and electrolyte balance of the body
All segments of the proximal tubule are capable of reabsorbing
the same solutes

Quantitatively, however, marked differences exist along the


tubule:
reabsorption of sodium, water, glucose and
bicarbonate in the early proximal tubule (S1) is about
three-fold greater than that in the mid-portion of
the convoluted proximal tubule (S2), and nearly ten
times that of the straight segment of the tubule (S3).
The rate of reabsorption along the proximal tubule is
therefore not constant or the same throughout the tubule

The early segments have a greater membrane surface area,


and more mitochondria.

In addition to the variable reabsorptive capacity between


the early and late proximal segments, in the earliest parts
of the proximal tubule (S1) there is also a preferential
reabsorption of organic solutes (glucose, and amino acids),
sodium bicarbonate, lactate, acetate, phosphate and citrate.
Transport of solutes out of the
proximal tubule can be described
to occur in two phases

In the first phase, essential


nutrients such as glucose, sodium
bicarbonate, and amino acids are
predominantly reabsorbed

The second phase predominantly


involves NaCl reabsorption

S1 S2 S3
Glucose reabsorption

Glucose reabsorption in the proximal tubule occurs in two steps

• Carrier mediated, Na+/glucose cotransport across the apical


membrane

(i) Followed by facilitated glucose transport and active sodium


extrusion

Two specific Na+ coupled carriers have been identified in the


apical membrane

- SGLT-1 and SGLT-2


These depend on the sodium gradient and glucose transport
is therefore a secondary active step as sodium gradient
has to be actively maintained

Transport of glucose across the basolateral membrane involves


the GLUT i.e. GLUT 2 in the early PT and GLUT 1 in the late
PT.
It is a passive process
Glucose reabsorption is maximum in the S1 segment and slows
as the tubular fluid progresses from S1 to S3

However the affinity for glucose rises from S1 to S3 as


indicated by the Km

(Km is defined as the concentration of substrate at which a half-maximal


rate of transport is attained)

The Km for S1 is about 2 mM and for S3 it is 0.4 mM

The different affinities for glucose in the different proximal


segments is due to the presence of the two SGLT carriers, i.e.
1 and 2.
SGLT-2 has a high capacity but low affinity and is found in the
early proximal tubule, whereas SGLT-1 has high affinity but
low capacity and is found in the late proximal tubule.

As the early part of the proximal tubule is in the outer cortex,


SGLT-2 is found predominantly located there, whereas SGLT-1
is found located in the outer medulla, where S3 is located.
Exit of glucose from the proximal tubular cells is via GLUT,
in particular GLUT2 and GLUT1, which is a high-capacity,
low affinity baso-lateral transporter found in tissues with large
glucose fluxes, such as intestine, liver, pancreas and proximal
tubule (S1 and S2).
GLUT2 mutation is present in humans who present with
Fanconi syndrome, which is glycosuria with generalised
proximal tubular dysfunction.
Properties of SGLT transporters
• SGLT-2 binds to one Na+ per glucose
• SGLT-1 carries two Na+ per glucose
1. SGLT-2 has high glucose carrying capacity

1. SGLT-1 has a low glucose carrying capacity


• SGLT-2 has a low affinity for glucose (Km 2 mM)
• SGLT-1 has a high affinity for glucose (Km 0.4 mM)

1. SGLT-1 has a Km for sodium of 50 mM


1. SGLT-2 has a Km for sodium of 228 mM

1. SGLT-1 has an affinity for D-galactose that is 10-fold higher than


SGLT-2
Patients with rare congenital disorder of glucose-galactose malabsorption
have a partial defect in renal reabsorption of glucose, whereas patients with
renal glycosuria have normal intestinal glucose transport.
Renal tubular glucose handling
Since glucose transport is carrier dependent it exhibits
saturation kinetics.

Renal threshold for glucose

Transport maximum TM
for glucose
In an adult human, the
transport maximum for
glucose is 375 mg/min
Reabsorption of sodium chloride (NaCl)

Sodium chloride reabsorption occurs along the entire nephron

Na+ is avidly reabsorbed with glucose, amino acids and


bicarbonate in the early part of the proximal tubule.
This can be considered the first phase.

The second phase of Na+ reabsorption is together with chloride


Both passive and active processes contribute to NaCl
reabsorption in the second phase

The percentage of passive NaCl absorption varies from one


third to two thirds of the total NaCl absorption in the second
phase of proximal absorption
Diffusion is probably the main driving force for passive
sodium transport in the second phase, in addition to the
lumen PD and Na+ gradient.

Both these forces are generated by the preferential active


reabsorption of sugar, amino acids and HCO3- in the first phase

The high Cl- concentration results in paracellular movement of


Cl- from the lumen to the peritubular plasma creating a lumen
positive PD, which then drives the passive paracellular sodium
transport
Active NaCl reabsorption in the second phase involves
electrogenic Na+ reabsorption, involving the basolateral Na+,
K+-ATPase

The entry of sodium into the tubular cell is favoured by the


low Na+ concentration inside the cell

The lumen-negative PD created by active sodium reabsorption


then also provides the driving force for paracellular Cl-
reabsorption
Renal handling of sodium chloride

Site of aldosterone action (2-3% of


filtered sodium is under humoral
control.

Aldosterone acts on principal cells


of CD.

Aldosterone increases apical


sodium channels, apical K+
channels, basolateral sodium
pump activity, and mitochondrial
metabolism.
Proximal tubular calcium reabsorption
About 55% of the total serum calcium is filterable at the glomerulus
98 – 99% of the filtered calcium is reabsorbed
The proximal tubule reabsorbs about 50-60% of the filtered calcium

Calcium reabsorption in the S2 segment of the proximal tubule is


mainly passive and paracellular

It parallels the reabsorption of sodium and water


Claudin-2 is proposed to be the paracellular calcium channel

There is also a possibility that there is active transport of Ca 2+,


which is transcellular involving passive movement of calcium into
the cell through epithelial calcium channels and then a basolateral
extrusion by Na+/Ca 2+ exchanger driven by Na+-K+ ATPase or
Ca 2+ - ATPase.
Calcium transport in the proximal tubule

The transcellular reabsorption probably accounts for about 10-15%


of the total calcium reabsorption in the proximal tubule and present
in the S1 segment of the PCT
(Note: Transcellular pathway is the major pathway in the TALH and DCT).

Proximal tubular reabsorption of calcium is decreased by volume expansion


and increased by volume depletion.
Calcium handling by the nephron

Effects of PTH

There are 2 types of PTH receptors.


PTH1R and PTH2R. PTH1R binds to
PTH and PTHrP, PTH2R binds only to
PTH.

Action.

At the glomerulus decreases kf


reducing gfr and filtered load of calcium,

In the proximal tubule PTH inhibit


NaHCO3-reabsorption calcium
reabsorption.

The increased distal delivery of HCO3-


Increases calcium reabsorption by
Increasing the apical calcium channels
and paracellular permeability
Magnesium reabsorption
70-80% of the serum magnesium is freely filtered at the glomerulus

Only about 3% of the filtered load appears in the urine

The proximal tubule reabsorbs between 5-15% of the filtered


magnesium load

The mechanism of magnesium reabsorption in the proximal tubule is not


clearly understood but may be paracellular and a passive process
Magnesium handling by the nephron
Potassium reabsorption

Potassium is freely filtered at the glomerulus


There is net potassium reabsorption in the early part of the
proximal tubule.
Approximately 65% of the filtered K+ is reabsorbed in the
proximal convoluted tubule mainly by the paracellular route

Under normal situations it is rigidly coupled to that of Na+ and


water

However, there occurs a net entry of K+ into the lumen at the


proximal straight tubule (S3) and the thin descending limb.
K+ reabsorption in the proximal tubule is primarily passive
and mainly paracellular

Weinstein proposed a model for this paracellular movement

There occurs

• A decrease in K+ conc in the lateral interspaces due to


active K+ uptake by the N+-K+-ATPase
ii) Low or absent diffusion from plasma to the interspace
iii) Diffusion of K+ from lumen to the lateral spaces
Potassium reabsorption in the proximal tubule
Potassium handling by the kidney
Phosphate reabsorption
Plasma phosphate concentration varies between 0.8 and 1.5 mM.

The filterable phosphate varies between 0.7 – 1.3 mM (ionised and complexed)
(i.e. 86 % of the total phosphate concentration).

mg/dl mM
Ionised H2PO4- and HPO42- 2.1 0.7
Diffusible phosphate 1.5 0.5
Non-diffusible phosphate 0.6 0.2
Total phosphate 4.2 1.4

At a blood pH of 7.4, 80% of the ionised phosphate is HPO42- and the


rest as H2PO4-

At a GFR of 180 litres/day approximately 7000 mg of phosphate is filtered


per day. Nearly 90% of the filtered phosphate is reabsorbed.

The proximal tubule reabsorbs 80% of the filtered load.


Phosphate reabsorption is sodium dependent and enters the apical membrane
by secondary active transport and leaves the basolateral membrane passively.

Phosphate-anion
exchanger

Proximal tubule
Water reabsorption

In the proximal tubule water movement from the tubular lumen


to the peritubular capillary is the passive consequence of active
solute reabsorption
It is determined by the transepithelial driving forces for water
and the passive transepithelial water permeability (Pf)

The Pf of the proximal tubule is very high, which allows small


osmotic pressure differences to drive water transport.

Both paracellular and transcellular pathways are believed to be


involved in the movement of water. The transcellular pathway
is more dominant.

Water moves across the apical membrane through aquaporins


(more details in the lecture on urine concentration mechanisms)
Amino acid transport.

The proximal tubule apical membrane transports all amino


acids
About 90% of the filtered load of amino acids is reabsorbed
in the first part of the proximal tubule.

The remaining 9-10% is reabsorbed in the late proximal


tubule
Amino acid transporters can be divided into two
major groups

• Na+ dependent
• Na+ independent
The AA transport systems have also been divided according
the AA transported

i) Neutral amino acid transporters


ii) Acid or anionic amino acid transporters
iii) Basic or cationic amino acid transporters

There are a smaller number of amino acid transport proteins


than there are amino acids, implying that some transporters
accept multiple amino acids
Transport of acidic amino acids (anionic transporters)

This transporter is responsible for the transport of aspartate


and glutamate

The acidic or cationic amino acid transporters carry a negative


charge, and the amino acid transport is coupled to the
transport of at least two Na+ ions or in some instances by a
countertransport of K+ and H+.
Transport of neutral amino acids

Two distinct amino acid transporters have been identified for


the transport of neutral amino acids

One of these transports all the three neutral amino acids


namely; glycine, proline, and hydroxyproline
The other transports glycine only.
Both however carry sodium and the glycine transporter also
carries chloride

Transport of basic amino acids (cationic transporters)

Amino acids lysine and arginine are transported by the same


amino acid transporter that transports the neutral amino acid
cystine.
L
Handling of amino acids along the nephron
THANK YOU
Amino acid transport systems found in the kidney