Tubular Reabsorption and Secretion

1. Introduction

With up to 180 liters per day passing through the nephrons of the kidney, it is quite obvious that most of that fluid and its contents must be reabsorbed. That recovery occurs in the proximal convoluted tubule (PCT), loop of Henle, distal convoluted tubule (DCT), and collecting ducts (see the areas in the image below). Various portions of the nephron differ in their capacity to reabsorb water and specific solutes.

While much of the reabsorption and secretion occur passively based on concentration gradients, the amount of water that is reabsorbed or lost is tightly regulated. This control is exerted directly by antidiuretic hormone (ADH) and aldosterone, and indirectly by renin. Recall that in a previous lesson, you learned that ADH is a hormone secreted by the hypothalamus that signals water reabsorption by the kidneys. Most water is recovered in the PCT, loop of Henle, and DCT. About 10% (about 18 L) reaches the collecting ducts. The collecting ducts, under the influence of ADH, can recover almost all of the water passing through them, in cases of dehydration, or almost none of the water, in cases of over-hydration.

learn more

In this lesson, you will be provided an overview of tubular reabsorption and secretion in the nephrons. To read more about how and where substances are secreted, absorbed, and filtered, please visit the supplemental document Secreted, Reabsorbed, and Filtered Substances in the Nephron.pdf.

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2. Mechanisms of Recovery

Mechanisms by which substances move across membranes for reabsorption or secretion include active transport, diffusion, facilitated diffusion, secondary active transport, and osmosis.

Active transport utilizes energy, usually the energy found in a phosphate bond of ATP, to move a substance across a membrane from a low to a high concentration. It is very specific and must have an appropriately shaped receptor for the substance to be transported. The transport of Na⁺ out of a cell and K⁺ into a cell by the Na⁺/K⁺ pump is an example of active transport. Both ions are moved in opposite directions from a lower to a higher concentration.

Simple diffusion moves a substance from a higher to a lower concentration down its concentration gradient. It requires no energy and only needs to be soluble.

Facilitated diffusion is similar to diffusion in that it moves a substance down its concentration gradient. The difference is that it requires specific membrane receptors or channel proteins for movement. The movement of glucose and, in certain situations, Na⁺ ions is an example of facilitated diffusion. In some cases of mediated transport, two different substances share the same channel protein port; these mechanisms are described by the terms symport and antiport.

Symport mechanisms move two or more substances in the same direction at the same time, whereas antiport mechanisms move two or more substances in opposite directions across the cell membrane. Both mechanisms may utilize concentration gradients maintained by ATP pumps. As described previously, when active transport powers the transport of another substance in this way, it is called “secondary active transport.” Glucose reabsorption in the kidneys is by secondary active transport. Na⁺/K⁺ ATPases on the basal membrane of a tubular cell constantly pump Na⁺ out of the cell, maintaining a strong electrochemical gradient for Na⁺ to move into the cell from the tubular lumen. On the luminal (apical) surface, a Na⁺/glucose symport protein assists both Na⁺ and glucose movement into the cell. The cotransporter moves glucose into the cell against its concentration gradient as Na⁺ moves down the electrochemical gradient created by the basal membranes Na⁺/K⁺ ATPases. The glucose molecule then diffuses across the basal membrane by facilitated diffusion into the interstitial space and from there into peritubular capillaries.

Most of the Ca²⁺, Na⁺, glucose, and amino acids must be reabsorbed by the nephron to maintain homeostatic plasma concentrations. Other substances, such as urea, K⁺, ammonia (NH₃), creatinine, and some drugs are secreted into the filtrate as waste products. Acid–base balance is maintained through actions of the lungs and kidneys: the lungs rid the body of H⁺, whereas the kidneys secrete or reabsorb H⁺ and HCO₃⁻ . In the case of urea, about 50% is passively reabsorbed by the PCT. More is recovered by the collecting ducts as needed. ADH induces the insertion of urea transporters and aquaporin channel proteins.

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3. Reabsorption and Secretion in the PCT

The renal corpuscle filters the blood to create a filtrate that differs from blood mainly in the absence of cells and large proteins. From this point to the ends of the collecting ducts, the filtrate undergoes modification through secretion and reabsorption before true urine is produced.

The first point at which the forming urine is modified is in the PCT. Here, some substances are reabsorbed, whereas others are secreted. Note the use of the term “reabsorbed.” All of these substances were “absorbed” in the digestive tract—99% of the water and most of the solutes filtered by the nephron must be reabsorbed. Water and substances that are reabsorbed are returned to the circulation by the peritubular and vasa recta capillaries.

It is important to understand the difference between the glomerulus and the peritubular and vasa recta capillaries. The glomerulus has a relatively high pressure inside its capillaries and can sustain this by dilating the afferent arteriole while constricting the efferent arteriole. This assures adequate filtration pressure even as the systemic blood pressure varies. The movement of water into the peritubular capillaries and vasa recta will be primarily influenced by osmolarity and concentration gradients.

The movement of many solutes and water from the PCT lumen into the interstitial spaces between cells occurs through two main pathways:

• The transcellular pathway, in which there is movement across the PCT cell luminal membrane into the cell and out of the cell through basolateral membranes.
• The paracellular pathway, in which movement goes around the PCT cells from the lumen through the tight junctions between the cells and into the interstitial spaces between cells.

In the transcellular pathway, there are specific membrane transporters involved:

• Active transport mostly involves the Na⁺/K⁺ pump on the basolateral side of the membrane, which maintains an inward Na⁺ gradient from the PCT lumen into the PCT cell by pumping Na⁺ from the cell to the interstitial spaces. This transport uses ATP since Na⁺ is being transported against its concentration gradient.
• Facilitated diffusion involves uniporters, symporters, and antiporters and is usually linked to the Na⁺ gradient, but sometimes to the gradient of other ions. The antiporters secrete substances from the inside of the cell to the PCT lumen. Some of these mechanisms also occur on the basolateral membrane to transport substances out of the PCT cells into the interstitial spaces.
• Osmosis results in the movement of water into the PCT cells through channels called aquaporins in response to an osmotic gradient, usually Na⁺. Aquaporins also exist on the basolateral membranes to move water from inside the PCT cell to the interstitial space, again in response to Na⁺ gradients created by the Na⁺/K⁺ pump.
• Conversion to gas can occur when bicarbonate combines with H⁺ in the PCT lumen to make carbonic acid. An enzyme called carbonic anhydrase on the luminal membrane of the PCT cell converts carbonic acid into carbon dioxide and water. The carbon dioxide moves freely across the luminal membrane. Once inside, carbonic anhydrase recombines carbon dioxide and water into carbonic acid which dissociates into bicarbonate and H⁺. Bicarbonate then moves to the interstitial spaces from the cell on a symporter linked to the Na⁺ gradient.

In the paracellular route, osmotic movements of water through the tight junctions between the cells are set up by the influx of sodium ions into the cells and the subsequent pumping of sodium ions from the cells into the interstitial spaces. As water moves osmotically, many different ions flow through the tight junctions with it. Essentially, these ions get dragged along by the water, which is why this mechanism is called “solvent drag.” Think of the solutes as surfers riding the “waves” of water through the tight junctions.

In the PCT, approximately ⅔ of the filtered Na⁺, K⁺, and H₂O are reabsorbed. All of the filtered glucose is reabsorbed. Most bicarbonate (80–90%) is reabsorbed. Phosphate (85%) is reabsorbed, but inhibited by parathyroid hormone (PTH).

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4. Reabsorption and Secretion in the Loop of Henle

The loop of Henle consists of two sections: thick and thin descending and thin and thick ascending sections. The loops of cortical nephrons do not extend into the renal medulla very far, if at all. Juxtamedullary nephrons have loops that extend variable distances, some very deep into the medulla. The descending and ascending portions of the loop are highly specialized to enable the recovery of much of the Na⁺ and water that was filtered by the glomerulus.

As the forming urine moves through the loop, the osmolarity will change from isosmotic with blood (about 278–300 mOsmol/kg) to both a very hypertonic solution of about 1200 mOsmol/kg and a very hypotonic solution of about 100 mOsmol/kg. These changes are accomplished by osmosis in the descending limb and active transport in the ascending limb. Solutes and water recovered from these loops are returned to the circulation by way of the vasa recta.

What is happening in the Loop of Henle:

• Na⁺ (25%) and K⁺ (20%) are reabsorbed in the thick ascending limb
• H₂O (15%) is reabsorbed only in the descending limb by osmosis
• Cl⁻ reabsorbed in the thin ascending limb by diffusion and in the thick ascending limb by diffusion and solvent drag
• HCO₃⁻ is reabsorbed in ascending limb
• Urea is secreted in the descending limb by diffusion
• Countercurrent flow and differences in permeability set up osmotic gradient in the medulla (low osmolarity in superficial layers → high osmolarity in deep layers)
• When filtrate leaves the loop, it is hypotonic compared to plasma

4a. Descending Loop

The majority of the descending loop consists of simple squamous epithelial cells; to simplify the function of the loop, this discussion focuses on these cells. These membranes have permanent aquaporin channel proteins that allow unrestricted movement of water from the descending loop into the surrounding interstitium as osmolarity increases from about 300 mOsmol/kg to about 1200 mOsmol/kg in the filtrate. This increase results in the reabsorption of up to 15% of the water entering the nephron. Modest amounts of urea, Na⁺, and other ions are also recovered here.

Most of the solutes that were filtered in the glomerulus have now been recovered along with the majority of water, about 82%. As the forming urine enters the ascending loop, major adjustments will be made to the concentration of solutes to create what you perceive as urine.

4b. Ascending Loop

The ascending loop is made of very short thin and longer thick portions. Once again, to simplify the function, this section only considers the thick portion. The thick portion is lined with simple cuboidal epithelium without a brush border. It is completely impermeable to water due to the absence of aquaporin proteins, but ions, mainly Na⁺ and Cl⁻, are actively reabsorbed by a cotransport system. This has two significant effects: removal of NaCl while retaining water leads to a hypoosmotic filtrate by the time it reaches the DCT; pumping NaCl into the interstitial space contributes to the hyperosmotic environment in the kidney medulla.

The Na⁺/K⁺ ATPase pumps in the basal membrane create an electrochemical gradient, allowing reabsorption of Cl⁻ by Na⁺/Cl⁻ symporters in the apical membrane. At the same time that Na⁺ is actively pumped from the basal side of the cell into the interstitial fluid, Cl⁻ follows the Na⁺ from the lumen into the interstitial fluid by a paracellular route by solvent drag.

Most of the K⁺ that enters the cell via symporters returns to the lumen (down its concentration gradient) through leaky channels in the apical membrane. Note the environment now created in the interstitial space: with the “back door exiting” K⁺, there is one Na⁺ and two Cl⁻ ions left in the interstitium surrounding the ascending loop. Therefore, compared with the lumen of the loop, the interstitial space is now a negatively charged environment. This negative charge attracts cations (Na⁺, K⁺, Ca²⁺, and Mg²⁺) from the lumen via a paracellular route to the interstitial space and vasa recta.

4c. Countercurrent Multiplier System

The structure of the loop of Henle and associated vasa recta create a countercurrent multiplier system. The countercurrent term comes from the fact that the descending and ascending loops are next to each other and their fluid flows in opposite directions (countercurrent). The multiplier term is because of the action of solute pumps that increase (multiply) the concentrations of urea and Na⁺ deep in the medulla.

As discussed above, the ascending loop actively reabsorbs NaCl out of the forming urine into the interstitial spaces. In addition, collecting ducts have urea pumps that actively pump urea into the interstitial spaces. This results in the recovery of NaCl to the circulation via the vasa recta and creates a high osmolar environment in the depths of the medulla.

did you know

Ammonia (NH₃) is a toxic byproduct of protein metabolism. It is formed as amino acids are deaminated by liver hepatocytes. That means that the amine group, NH₂, is removed from amino acids as they are broken down. Most of the resulting ammonia is converted into urea by liver hepatocytes. Urea is not only less toxic but is utilized to aid in the recovery of water by the loop of Henle and collecting ducts.

At the same time that water is freely diffusing out of the descending loop through aquaporin channels into the interstitial spaces of the medulla, urea freely diffuses into the lumen of the descending loop as it descends deeper into the medulla, much of it to be reabsorbed from the forming urine when it reaches the collecting duct. Thus, the movement of Na⁺ and urea into the interstitial spaces by these mechanisms creates the hyperosmotic environment of the medulla. The countercurrent multiplier system of the loop of Henle sets up an osmotic gradient from low in superficial portions to high in deep portions of the medulla. This gradient is important in recovering both water from the collecting ducts as you will see below.

As the loop turns to become the ascending loop, there is an absence of aquaporin channels, so water cannot leave the loop. However, in the basal membrane of cells of the thick ascending loop, ATPase pumps actively remove Na+ from the cell. A Na⁺/K⁺/2Cl⁻ symporter in the apical membrane passively allows these ions to enter the cell cytoplasm from the lumen of the loop down a concentration gradient created by the pump. This mechanism works to dilute the fluid of the ascending loop ultimately to approximately 50–100 mOsmol/L.

At the transition from the DCT to the collecting duct, about 20% of the original water is still present and about 10% of the sodium. If no other mechanism for water reabsorption existed, about 20–25 liters of urine would be produced. Now consider what is happening in the adjacent capillaries, the vasa recta. They are recovering both solutes and water at a rate that preserves the countercurrent multiplier system.

In general, blood flows slowly in capillaries to allow time for the exchange of nutrients and wastes. In the vasa recta particularly, this rate of flow is important for two additional reasons. First, the flow must be slow to allow blood cells to lose and regain water without either crenating or bursting. Second, a rapid flow would remove too much Na⁺ and urea, destroying the osmolar gradient that is necessary for the recovery of solutes and water. Thus, by flowing slowly to preserve the countercurrent mechanism, as the vasa recta descend, Na⁺ and urea are freely able to enter the capillary, while water freely leaves; as they ascend, Na⁺ and urea are secreted into the surrounding medulla, while water reenters and is removed.

term to know

Countercurrent Multiplier System

A system that involves the descending and ascending loops of Henle directly forming urine in opposing directions to create a concentration gradient when combined with variable permeability and sodium pumping.

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5. Reabsorption and Secretion in the DCT

Approximately 80% of filtered water has been recovered by the time the dilute forming urine enters the DCT.

What is happening in the early DCT:

• Na⁺ (5%) is reabsorbed by the Na channel and is sensitive to aldosterone
• K⁺ is secreted by the K channel and is sensitive to aldosterone
• Both Na⁺ and K⁺ movements in combination with the basolateral Na⁺/K⁺ pump are sensitive to aldosterone
• H₂O (8%) is reabsorbed by osmosis and is sensitive to aldosterone
• Cl⁻ is reabsorbed by diffusion
• Ca²⁺ is reabsorbed by the PTH-stimulated Ca channel on the apical side in combination with the Ca pump on the basolateral side

The DCT will recover another 10%–15% before the forming urine enters the collecting ducts. Aldosterone increases the amount of Na⁺/K⁺ ATPase in the basal membrane of the DCT and collecting duct. The movement of Na⁺ out of the lumen of the collecting duct creates a negative charge that promotes the movement of Cl⁻ out of the lumen into the interstitial space by a paracellular route across tight junctions. Peritubular capillaries receive the solutes and water, returning them to the circulation.

Cells of the DCT also recover Ca²⁺ from the filtrate. Receptors for parathyroid hormone (PTH) are found in DCT cells and when bound to PTH, induce the insertion of calcium channels on their luminal surface. The channels enhance Ca²⁺ recovery from the forming urine. In addition, as Na⁺ is pumped out of the cell, the resulting electrochemical gradient attracts Ca²⁺ into the cell.

Finally, calcitriol (1,25 dihydroxy vitamin D, the active form of vitamin D) is very important for calcium recovery. It induces the production of calcium-binding proteins that transport Ca²⁺ into the cell. These binding proteins are also important for the movement of calcium inside the cell and aid in the exocytosis of calcium across the basolateral membrane. Any Ca²⁺ not reabsorbed at this point is lost in the urine.

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6. Collecting Ducts and Recovery of Water

Solutes move across the membranes of the collecting ducts, which contain two distinct cell types, principal cells and intercalated cells. A principal cell possesses channels for the recovery or loss of sodium and potassium. An intercalated cell secretes or absorbs acid or bicarbonate. As in other portions of the nephron, there is an array of micromachines (pumps and channels) on display in the membranes of these cells.

What is happening in late DCT and collecting ducts:

• Principal cells:
  • Na⁺ (5%) is reabsorbed (Na channel)
  • K⁺ is secreted (K channel)
  • Both in combination with basolateral Na/K pump sensitive to aldosterone
  • Intercalated cells reabsorb K⁺ and HCO₃⁻, while secreting H⁺ (Na-HCO₃⁻-symport, Cl⁻-HCO₃⁻-antiport)
• H₂O (8%) is reabsorbed by osmosis and sensitive to ADH
• Cl⁻ is reabsorbed by diffusion
• Urea is secreted by diffusion

Regulation of urine volume and osmolarity are major functions of the collecting ducts. By varying the amount of water that is recovered, the collecting ducts play a major role in maintaining the body’s normal osmolarity.

key concept

If the blood becomes hyperosmotic, the collecting ducts recover more water to dilute the blood; if the blood becomes hypoosmotic, the collecting ducts recover less of the water, leading to concentration of the blood. Another way of saying this is: if plasma osmolarity rises, more water is recovered and urine volume decreases; if plasma osmolarity decreases, less water is recovered and urine volume increases.

This function is regulated by the posterior pituitary hormone ADH (vasopressin). With mild dehydration, plasma osmolarity rises slightly. This increase is detected by osmoreceptors in the hypothalamus, which stimulates the release of ADH from the posterior pituitary. If plasma osmolarity decreases slightly, the opposite occurs.

When stimulated by ADH, aquaporin channels are inserted into the apical membrane of principal cells, which line the collecting ducts. As the ducts descend through the medulla, the osmolarity surrounding them increases (due to the countercurrent mechanisms described above). If aquaporin water channels are present, water will be osmotically pulled from the collecting duct into the surrounding interstitial space and into the peritubular capillaries. Therefore, the final urine will be more concentrated.

did you know

Urine is generally darker in the morning because it is more concentrated. You do not drink water at night, so ADH secretion goes up and more water is reabsorbed from the collecting ducts, which concentrates your urine. The urine appears darker because the concentration of urea is higher.

If less ADH is secreted, fewer aquaporin channels are inserted and less water is recovered, resulting in dilute urine. By altering the number of aquaporin channels, the volume of water recovered or lost is altered. This, in turn, regulates the blood osmolarity, blood pressure, and osmolarity of the urine.

As Na⁺ is pumped from the forming urine, water is passively recaptured for circulation; this preservation of vascular volume is critically important for the maintenance of normal blood pressure. Aldosterone is secreted by the adrenal cortex in response to angiotensin II stimulation. Recall that you previously learned that angiotensin II is an extremely potent vasoconstrictor that functions immediately to increase blood pressure. By also stimulating aldosterone production, it provides a longer-lasting mechanism to support blood pressure by maintaining vascular volume (water recovery).

In addition to receptors for ADH, principal cells have receptors for the steroid hormone aldosterone. While ADH is primarily involved in the regulation of water recovery, aldosterone regulates Na⁺ recovery. Aldosterone stimulates principal cells to manufacture luminal Na⁺ and K⁺ channels as well as Na⁺/K⁺ ATPase pumps on the basal membrane of the cells.

key concept

When aldosterone output increases, more Na⁺ is recovered from the forming urine and water follows the Na⁺ passively. As the pump recovers Na⁺ for the body, it is also pumping K⁺ into the forming urine, since the pump moves K⁺ in the opposite direction. When aldosterone decreases, more Na⁺ remains in the forming urine and more K⁺ is recovered in the circulation.

Symport channels move Na⁺ and Cl⁻ together. Still, other channels in the principal cells secrete K⁺ into the collecting duct in direct proportion to the recovery of Na⁺.

Intercalated cells also play significant roles in regulating blood pH. Intercalated cells reabsorb K⁺ and HCO₃⁻ while secreting H⁺. This function lowers the acidity of the plasma while increasing the acidity of the urine.

watch

Please watch the following video for more information on this topic.

terms to know

Principal Cell

A cell found in collecting ducts and possess channels for the recovery or loss of sodium and potassium; under the control of aldosterone; also have aquaporin channels under ADH control to regulate recovery of water.

Intercalated Cell

A specialized cell of the collecting ducts that secretes or absorbs acid or bicarbonate; important in acid–base balance.

make the connection

If you're taking the Anatomy & Physiology II Lab course simultaneously with this lecture, it's a good time to try the Lab Renal Physiology: Find the mode of action of a diuretic drug in Unit 4 of the Lab course. Review the lab-to-lecture crosswalk if you need more information. Good luck!