Regulation of Water Balance

Water Reabsorption

Water reabsorption is a passive process: water is reabsorbed by osmosis. In most of the nephron there is unregulated isosmotic reabsorption of water and solute, in other words, water reabsorption is coupled to solute reabsorption. However, it is possible to reabsorb water independently of solute to produce a concentrated urine, that is, urine that has a higher osmolarity than the extracellular fluid.

Regulated water reabsorption occurs from the medullary collecting duct.
The figure at left is a schematic showing the last part of a nephron.  The ability to excrete urine that is more concentrated than the extracellular fluid (ECF) depends upon the loops of Henle, which function to concentrate osmolarity in the deepest part of the medulla, creating a vertical osmotic gradient. As the collecting duct descends through the medulla, the increasing osmolarity in the surrounding interstitial fluid drives water reabsorption.

However, there is a tremendous variability in water excretion. The urine produced can either be concentrated, or very dilute. How do the kidneys vary their urine concentrating ability? They do so by regulating water permeability in the collecting duct.

Regulated Permeability in the Collecting Duct

In humans, the vertical osmotic gradient in the medulla allows the kidneys to produce urine that can be roughly 5 times as concentrated as the ECF. Urine concentration can be varied through the regulation of water permeability in the collecting duct.

The permeability of cell membranes to water depends upon the presence of water channels known as aquaporins. There is a family of aquaporin proteins, with different types being expressed in different tissues. AQP3 (blue in figure) is constitutively expressed on the basolateral surface of cells in the collecting duct. AQP2 is found on the apical surface of these cells, but the number of AQP2 channels on the membrane is regulated by the hormone vasopressin (also known arginine vasopressin and as antidiuretic hormone or ADH). When vasopressin binds to its receptor on the collecting duct cells, it stimulates the translocation of AQP2 to the membrane by causing vesicles containing the protein to fuse with the plasma membrane.  The result is more AQP2 proteins on the apical membrane and higher permeability to water.

Regulation of Vasopressin Secretion

Vasopressin is a peptide hormone that is produced by neurosecretory cells, a type of endocrine cell found in the hypothalamus.  As shown in the figure, neurosecretory cells have dendrites, axons, and terminals just like typical neurons. The difference is that the terminals of neurosecretory cells are adjacent to capillaries. Neurosecretory cells secrete regulatory molecules (green dots) that enter the circulation and act as hormones.

Vasopressin is secreted by neurosecretory cells whose cell bodies are in the hypothalamus and whose terminals are located in the posterior pituitary (also called the neurohypophysis). The main control of vasopressin secretion is by the osmoreceptors, neurons that sense changes in the osmolarity of the extracellular fluid. The osmoreceptors are also located in the hypothalamus.  If the osmolarity of the ECF increases, the osmoreceptors increase their frequency of action potential firing, and more vasopressin is secreted. Increased action potential firing by the osmoreceptors also stimulates thirst.  If the osmolarity of the ECF decreases, the osmoreceptors decrease their action potential frequency and less vasopressin is secreted.

Disorders in the Ability to Concentrate Urine (AVP-D and AVP-R)

If there is a problem with vasopressin action, the result is an inability to concentrate urine, which leads to polyuria (a high urine volume).  This can be caused by a lack of vasopressin (arginine vasopressin deficiency* or AVP-D; formerly known as central diabetes insipidus) or due to a defect in the ability of the kidney to respond to vasopressin (arginine vasopressin resistance or AVP-R; formerly known as nephrogenic diabetes insipidus). AVP-D may be caused by a genetic mutation where vasopressin is missing or defective. Head trauma, a tumor, or injury to the posterior pituitary may also cause AVP-D. AVP-D is treated with desmopressin, a synthetic vasopressin agonist.

AVP-R may be caused by a defect in the vasopressin receptor. Another type of mutation that causes the disorder involves a defect in the gene for AQP2. This defect prevents the proper localization of AQP2 proteins on the apical membrane of collecting duct cells. The drug lithium, which is used in the treatment of bipolar disorder, can cause acquired AVP-R.

*Clinicians refer to vasopressin as arginine vasopressin, the human form of vasopressin which contains an arginine in the 8th position of the nine-amino acid vasopressin peptide.

Summary: Homeostasis of ECF Osmolarity

The figure illustrates the regulation of water balance as a negative feedback regulatory system. The regulated variable is the ECF osmolarity. The sensors are the hypothalamic osmoreceptors, which modulate their frequency of action potential firing in response to changes in ECF osmolarity. The effector system that restores ECF osmolarity to its set point involves vasopressin and its effects on water reabsorption in the collecting duct.