Proximal Convoluted Tubule

Structure

The proximal convoluted tubule (PCT) is highly specialised for reabsorption and is the longest and most functionally significant segment of the renal tubule. It reclaims the majority of the glomerular filtrate (180L per day), reabsorbing approximately 130L (~70%) per day.

The PCT is lined with simple cuboidal epithelial cells with several adaptations. They possess a dense apical brush border (microvilli) increasing the surface area for reabsorption, as well as extensive basolateral membrane infoldings increasing the surface area for transporters. They also contain many mitochondria to power the transport of ions and substances.

The proximal convoluted tubule can be divided into 2 sections:

• The pars convoluta – located in the renal cortex. It can be further sub-divided into 2 segments; S1 (segment 1) and the proximal part of S2.
• The pars recta – a straight segment located in the outer medulla. It forms the distal part of S2 and S3

By --Uwe Gille 13:16, 13 May 2006 (UTC) (Own work) [GFDL, CC-BY-SA-3.0 or CC BY-SA 2.5-2.0-1.0], via Wikimedia Commons

Figure 1
Histology of the nephron. The following structures are shown: 1 (Glomerulus), 2 (PCT) and 3 (DCT).

Principles of Reabsorption

Water and solutes are reabsorbed from the PCT back into the bloodstream. In the PCT this mainly occurs via bulk transport, relying on concentration and pressure gradients and solvent drag created by bulk flow of water. In this way, solutes and water move from the PCT to the interstitium and then into peritubular capillaries.

Reabsorption in the proximal tubule is isosmotic. This means solutes and water are reabsorbed proportionally maintaining a constant tubular fluid osmolality (~300 mOsm/kg).

The PCT reabsorbs about:

• 65% of water, sodium, potassium and chloride
• 100% of glucose and amino acids
• 85-90% of bicarbonate

Secondary Active Transport

The driving force for reabsorption in the PCT is the movement of sodium (Na⁺) which provides the energy required for the transport of other substances. This is facilitated by the Na⁺/K⁺ ATPase pump on the basolateral membrane of epithelial cells. Three Na⁺ ions are actively transported out of the cell in exchange for two K⁺ ions, consuming ATP in the process.

The continuous removal of Na⁺ from the cell creates a low intracellular Na⁺ concentration. This establishes a strong electrochemical gradient favouring the movement of Na⁺ from the tubular lumen into the cell.

This electrochemical gradient powers, whilst consuming energy to create, powers secondary active transport mechanisms. This allows solutes such as glucose, amino acids, and phosphate to be reabsorbed against their own concentration gradients.

Transport Routes

Substances can be reabsorbed across the PCT epithelium via two main pathways:

• transcellularly – solutes pass directly through epithelial cells by crossing both the apical and basolateral membranes
• paracellularly – substances move between adjacent cells through tight junctions and intercellular spaces

Sodium-dependent transport is central to transcellular reabsorption. Sodium typically enters the cell with another solute via symporters on the apical membrane. Symporters are transporters that move two (or more) molecules in the same direction.

Sodium-glucose linked transporters (SGLTs) simultaneously transport sodium and glucose from the lumen into the cell in this way. Once inside, glucose  passively exits the cell at the basolateral membrane down its concentration gradient via facilitated diffusion. Amino acids are also reabsorbed via symporters.

Sodium can also be exchanged for other ions via antiporters. These are transporters that move two (or more) molecules in opposite directions. For example, the Na⁺/H⁺ exchanger allows sodium to enter the cell while hydrogen ions are secreted into the tubular lumen. This exchanger plays an important role in regulating acid-base balance.

BallenaBlanca (CC BY 4.0 [https://creativecommons.org/licenses/by/4.0/deed.en]), via Wikimedia Commons

Figure 2
Transcelluar vs paracellular transport

Bicarbonate Reabsorption

85% of bicarbonate is reabsorbed in the PCT, occurring through an indirect mechanism. Hydrogen ions secreted into the tubular lumen via the Na⁺/H⁺ exchanger, combine with filtered bicarbonate ions to form carbonic acid. This carbonic acid is converted into CO₂ and water in the lumen by the enzyme carbonic anhydrase.

The CO₂ produced diffuses into the epithelial cell, where it is converted back into carbonic acid by intracellular carbonic anhydrase before dissociating into hydrogen ions and bicarbonate.

The hydrogen ions are recycled back into the lumen via the Na⁺/H⁺ exchanger, while bicarbonate is transported across the basolateral membrane into the bloodstream, often alongside sodium ions. This is further detailed here.

Chloride Handling

The early PCT (S1) is relatively impermeable to Cl⁻. Thus, it is not significantly reabsorbed alongside water, increasing its luminal concentration further along the tubule. In later segments (S2 and S3) Cl⁻ reabsorption occurs passively, down its chemical gradient, primarily via paracellular diffusion.

The movement of negatively charged chloride ions in these later segments generates a slight positive charge within the tubular lumen (~+4 mV). This electrical gradient promotes the paracellular reabsorption of cations, including K⁺, Ca²⁺ and Mg²⁺.

Urea is reabsorbed through a similar mechanism to chloride.

Movement of Water

In the PCT, large volumes of solute are reabsorbed into the interstitium and bloodstream. Therefore, solute concentration decreases along the length of the tubule whilst it increases in the interstitium. This creates an osmotic gradient that drives the movement of water out of the tubular lumen via osmosis.

Water is largely reabsorbed paracellularly but it can take the transcellular route through aquaporin channels.

M. Koeppen, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons

Figure 3
Diagram showing ion absorption and secretion within the proximal convoluted tubule.

Secretion

In addition to reabsorption, the PCT plays an important role in secretion. This is when substances are excreted from the peritubular capillaries into the tubular lumen. Since only 20% of the blood is filtered in the glomerulus every minute, this provides an alternative route for substances to enter the tubular lumen.

The PCT secretes:

• Organic acids and bases – waste products of metabolism e.g. bile salts, oxalate and catecholamines
• Hydrogen ions (H⁺) – secretion is used to reabsorb bicarbonate (and Na⁺) in a 1:1 ratio maintaining acid/base balance. As hydrogen is ultimately reabsorbed and recycled for this purpose it is not ultimately excreted
• Drugs/toxins – secretion of organic cations (e.g. dopamine, morphine) occurs via the H⁺/OC⁺ exchanger on the apical side of the tubule cell and is driven by the Na⁺/H⁺ antiporter.

A summary of the most important transporter in the PCT is included in the table:

Clinical Relevance

Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common primary renal malignancy, typically originating from epithelial cells of the PCT.

It has been linked to hereditary or de novo mutations in chromosome 3, particularly affecting tumour suppressor genes such as the von Hippel–Lindau (VHL) gene. It most commonly affects men between the ages of 50-70 and is associated with smoking and obesity.

By Nephron (Own work) [CC BY-SA 3.0], via Wikimedia Commons

Figure 4
Histology of the kidney showing normal tissue on the left of the image and renal cell carcinoma on the right of the image.

RCC can present with:

• Haematuria
• Abdominal pain – particularly in the flanks
• Fever
• Weight loss
• Night sweats

The tumour can invade into the renal vein and further into the inferior vena cava. From here, it can metastasize hematogenously to lung and bones.

RCC can also have paraneoplastic effects, including Cushing-like symptoms and hypercalcaemia, caused by the release of adreno-corticotropic hormone (ACTH) or parathyroid hormone-related protein (PTHrP) respectively.

Treatment includes nephrectomy, radiotherapy and chemotherapy.