PROXIMAL TUBULAR FUNCTION

Professor Harbindar Jeet Singh Faculty of Medicine Universiti Teknologi Malaysia

Objectives of the lecture 1. 2. Characteristics of the proximal tubule 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 Proximal tubule Pars convoluta (PCT) (convoluted part) Proximal straight tubule (PST) (straight part) Ultrastructural S1-segment S2-segment S3-segment

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 • • 1. 1. • • 1. 1. 1. SGLT-2 binds to one Na+ per glucose SGLT-1 carries two Na+ per glucose SGLT-2 has high glucose carrying capacity 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) SGLT-1 has a Km for sodium of 50 mM SGLT-2 has a Km for sodium of 228 mM 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 Clreabsorption

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 HCO3Increases 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). Ionised H2PO4- and HPO42Diffusible phosphate Non-diffusible phosphate Total phosphate mg/dl 2.1 1.5 0.6 4.2 mM 0.7 0.5 0.2 1.4

At a blood pH of 7.4, 80% of the ionised phosphate is HPO42- and the rest as H2PO4At 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.
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Handling of amino acids along the nephron

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Amino acid transport systems found in the kidney

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