Control of Plasma Volume

Reabsorption in the Nephron

The process of sodium reabsorption is mainly active (i.e. needs ATP to occur), and is largely due to the action of Na-K-ATPase pumps on the basolateral membrane (the side of the cell facing the blood). Chloride (Cl^-) reabsorption is closely linked to sodium handling, so in many parts of the nephron Na⁺ reabsorption is accompanied by Cl^- movement.

Different segments of the nephron have different transporters for sodium in the apical (filtrate side) membrane:

• PCT:
  
  • Na-H Antiporter
  • Na-Glucose Symporter
  • Na-AA (Amino Acid) Co-transporter
  • Na-Pi (inorganic phosphate) co-transporter
• Loop of Henle
  • Sodium-Potassium-2Chloride (NKCC2) symporter (a transporter that carries these ions in together; it is the site of action of loop diuretics such as furosemide)
• Early DCT
  
  • NaCl symporter
• Late DCT and CD
  
  • Epithelial Na⁺ channels (ENaC)

Please note, this is not a complete list; there are many other types of sodium transporters.

Diagram - The difference between the apical and basolateral membranes of the nephron cells. This is important to understand before trying to understand the transporters in the nephron

SimpleMed original by Dr. Maddie Swannack

Diagram - The different types of transport across cell membranes. Uniport moves one substance in one direction, symport moves two or more substances in the same direction, and antiport moves two substances in opposite directions across the cell membrane

SimpleMed original by Dr. Maddie Swannack

Reabsorption in the Proximal Convoluted Tubule 

The PCT is split into three segments, based on the transporters that are present in the membrane: S1, S2, and S3.

In S1, 1 Na⁺ ion is co-transported with glucose across the apical membrane through SGLT2 (sodium-glucose co-transporter 2). Sodium is then actively transported into the capillary across the basolateral membrane through Na-K-ATPase and glucose moves into the capillary in its own transporter.

Diagram - An overview of sodium transporters in S1 of the PCT. Note there are other transporters, and not all sodium and glucose move directly from the cells to the capillary (some move first into the paracellular space, the gap between neighbouring cells)

SimpleMed original by Dr. Joshua Sturgeon

In S1 and S2, bicarbonate (HCO₃^-) is reabsorbed preferentially along with sodium, so the filtrate becomes relatively rich in Cl^- as it moves along the PCT. This creates a concentration gradient for the reabsorption of Cl^- in S2 and S3.

In S2 and S3, there is again Na-K-ATPase on the basolateral membrane; however, the apical membrane differs significantly.

Na⁺ is reabsorbed through the Na-H exchanger (the same Na-H antiporter described above) and Cl^- is reabsorbed in exchange for formate ions (HCOO^-). The H⁺ and HCOO^- ions are provided by methanoic acid (also called formic acid, HCOOH), which readily diffuses across the apical membrane and breaks up into its constituent ions inside the cell. These ions can then be exchanged with Na⁺ and Cl^-. This formate exchange is only one route for Cl^- reabsorption; Cl^- is also reabsorbed between the cells (the paracellular route), down the concentration gradient described above.

Cl^- moves into the capillaries through co-transport with K⁺ which was brought into the cell via Na-K-ATPase on the basolateral membrane.

Aquaporin channels (AQP) are also present here, which allow water to move from the apical membrane through the cells and out of the basolateral membrane. Water is also able to move into the paracellular space (the space in between cells), and the water moved by these two methods can then move into the capillary.

Diagram - An overview of sodium and chloride transporters in S2 and S3 of the PCT

SimpleMed original by Dr. Joshua Sturgeon

About 65% (about two-thirds) of the filtered water is reabsorbed in the PCT. This reabsorption is driven by several factors. Firstly, an osmotic gradient is generated by solute reabsorption so there is an increased osmolarity in the interstitial spaces. As a result, water moves out of the PCT into the interstitium down an osmotic gradient, and is then taken up into the capillaries due to their low hydrostatic pressure. Finally, oncotic forces (the pull that plasma proteins exert on water) in the capillary around the tubule act to bring water into the capillary, because the plasma proteins stay in the blood and are concentrated in this capillary after almost protein-free fluid was filtered out at the glomerulus.

Reabsorption in the Loop of Henle

The descending limb of the Loop of Henle (LoH) is permeable to water, so water moves out of the filtrate and into the capillaries by osmosis. This is because there is a higher concentration of Na⁺ in the interstitial fluid and capillary due to PCT reabsorption. The descending limb is impermeable to Na⁺ and Cl^-. This loss of water therefore creates an increased concentration of Na⁺ and Cl^- in the lumen of the descending limb, ready for active transport in the ascending limb.

Initially, in the thin portion of the ascending LoH, the high concentration of Na⁺ allows for passive reabsorption of ions through the paracellular route.

In the thick ascending LoH this concentration gradient of Na⁺ has diminished as some of the Na⁺ has already moved out passively, so Na⁺ is actively transported out of the lumen by NKCC2 transporters; some Na⁺ also crosses between the cells (the paracellular route). The Na⁺ ions can then move into the interstitium and capillaries by Na-K-ATPase.

Cl^- moves into the interstitium in its own transporter. At this point, in the filtrate, there is a lack of K⁺ ions as they were transported with Na⁺ and Cl^- in NKCC2. For this reason, it is vital that K⁺ ions diffuse back into the lumen of the LoH and this is done through the Renal Outer Medullary Potassium Channel (ROMK). This K⁺ recycling also leaves the lumen positively charged, which drives the paracellular reabsorption of Ca²⁺ and Mg²⁺ (calcium and magnesium ions). This region of the nephron has a very high energy (ATP) demand, so, like the S3 segment of the PCT, it is particularly sensitive to hypoxia (low oxygen supply to the tissue).

Diagram - An overview of the various transporters present in the thick ascending LoH. Remember solutes that end up in the interstitium will diffuse into the capillary

SimpleMed original by Dr. Joshua Sturgeon

Reabsorption in the Distal Convoluted Tubule

Due to the action of the thick ascending LoH, filtrate entering the DCT is hypo-osmotic (dilute) compared to plasma. The DCT is split into two regions: DCT 1 (the early part of the DCT) and DCT 2 (the late part of the DCT).

In DCT 1, NaCl enters across the apical membrane via a sodium-chloride co-transporter (NCC). This transporter is described as electroneutral as the 1⁺ charge from Na⁺ is cancelled-out by the 1^- charge from the Cl^-. Na⁺ is then transported into the capillary through Na-K-ATPase on the basolateral membrane, and the Cl^- diffuses across a channel due to the high concentration in the cell. The NCC co-transporter is of clinical importance as it is the site of action of thiazide diuretics.

Calcium (Ca²⁺) ions are also reabsorbed in the DCT. Ca²⁺ is transported across the apical membrane, after which it is immediately bound by calbindin, a protein that needs vitamin D. Calbindin then shuttles Ca²⁺ to the basolateral membrane where it is transported out into the interstitium through the sodium-calcium exchanger (NCX). This process is tightly regulated by hormones such as parathyroid hormone (PTH) and 1,25-dihydroxy-vitamin D (also known as activated Vitamin D and Calcitriol).

In DCT 2, Na⁺ enters across the apical membrane through both ENaC and NCC, and NCC remains important in this segment. Na⁺ is transported across the basolateral membrane by Na-K-ATPase. ENaC is another transporter (a sodium channel) of clinical importance as it is the site of action of amiloride (potassium-sparing) diuretics, which block ENaC in the principal cells of the late DCT and the cortical collecting duct. The movement of Na⁺ through ENaC is not electroneutral as there is no Cl^- that is being co-transported, so Cl^- diffuses through the tight junctions between the cells (paracellular uptake) to maintain the electroneutrality.

Diagram - An overview of the various transporters in the DCT with a DCT 1 typical cell above, and a DCT 2 typical cell below. Annotated in gold are the diuretics which have a site of action in the DCT. Remember that solutes which end up in the interstitium will eventually diffuse into the capillary

SimpleMed original by Dr. Joshua Sturgeon

Reabsorption in the Collecting Ducts

The DCT and the early part of the collecting duct (CD) share many similarities, and it is difficult to distinguish an exact transition from one cell type to another. The collecting duct can be divided into the cortical CD (in the outer part of the kidney, the cortex) and the medullary CD (in the inner part, the medulla) - this section focuses on the cortical CD.

There are two types of cells found in the cortical CD:

• Principal Cells - these make up 70% of the cells in the cortical CD and are responsible for the reabsorption of Na⁺ through ENaC (as was the case in DCT 2).
• Intercalated Cells - there are two types of intercalated cells. They are primarily involved in acid-base balance.
  
  • Type A Intercalated Cells (acid-secreting cells) secrete H⁺ ions into the lumen via proton pumps, with bicarbonate returned to the blood across the basolateral membrane.
  • Type B Intercalated Cells (base-secreting cells) secrete bicarbonate (HCO₃^-) into the lumen via a Cl^-/HCO₃^- exchanger, resulting in chloride reabsorption.

Sodium moves out of principal cells through Na⁺/K⁺ ATPase.

In principal cells, K⁺ that moves into the cell through the basolateral membrane is transported into the lumen through ROMK.

Principal cells can take up variable amounts of water depending on the number of aquaporin channels present in the apical membrane - this is under the influence of antidiuretic hormone (ADH).

In both type A and B intercalated cells, Cl^- moves across the basolateral membrane, into the capillary through various transporters.

Edited by: Dr. Maddie Swannack

Reviewed by: Dr. Thomas Burnell and Dr. Marcus Judge