Role of Aquaporins in Water Balance Disorders
| Title: | Role of Aquaporins in Water Balance Disorders |
|---|---|
| Authors: | Knepper, Mark; Nielsen, Soren; Verbalis, M.D., Joseph G. |
| Publisher: | Nephrology and Hypertension -- Current Opinion |
| Date Published: | July 01, 1997 |
| Reference Number: | 154 |
The aquaporins are a recently recognized family of water channels that mediate water transport in kidney and in other organs. Aquaporin-2, "vasopressin-regulated water channel", is regulated by vasopressin in two ways to account for overall control of collecting duct water permeability. First, vasopressin has a short-term effect in triggering translocation of aquaporin-2-containing intracytoplasmic vesicles to the apical plasma membrane, thus increasing principal cell water permeability. Second, vasopressin has a long-term effect in increasing the abundance of aquaporin-2 in collecting duct principal cells, increasing the maximal attainable water permeability. Using animal models, defects in these control mechanisms have been shown to be associated with several disorders of water balance, including central diabetes insipidus, congenital nephrogenic diabetes insipidus, acquired diabetes insipidus, syndrome of inappropriate antidiuretic hormone secretion, and several extracellular fluid volume expanded states.
This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
Vasopressin (VP), the antidiuretic hormone, regulates the action of AQP2 in both a short-term and a long-term manner in order to promote water permeability of the principal cells of the collecting duct. In short term regulation, VP links up to a vasopressin-2 receptor to increase the levels of an important metabolic regulator called cAMP. This triggers the movement of AQP2 to the apex of the collecting duct cell membranes, which gives them a great number of channels through which water may transport. This effect is called short-term regulation because the water permeability of the cell increases within a few minutes of the VP link-up to the vasopressin-2 receptor, and this increase is rapidly reversible.
VP regulates the water permeability of the collecting duct cells in a long-term way by increasing the number of AQP2s that are in the cells. The increase in numbers of AQP2 is a response to prolonged high levels of circulating VP. It takes at least 24 hours before the number of AQP2s start to rise, and the action is not rapidly reversible. So when VP binds with its receptor, AQP2 fuses with the apex of the cell membranes to increase their permeability. And when VP circulates for at least 24 hours, the number of AQP2 available to go to the cell membranes increases. Both short and long-term regulation of AQP2 by VP depends on its ability to link up with the vasopressin-2 receptor.
When defects in these regulating mechanisms occur, it can result in disorders of water balance such as central diabetes insipidus (CDI), congenital and acquired nephrogenic diabetes insipidus (NDI), syndrome of inappropriate antidiuretic hormone secretion (SIADH), and several extracellular fluid volume expanded states. Knepper, et al., examined a number of these disorders in rats to see if impairment of short and/or long-term VP regulation of AQP2 were associated with them. This gave them insight into the mechanics of these disorders as they occur in humans.
In CDI there is a long-term decrease in the amount of circulating VP levels which results in decreased levels of AQP2 in the kidney, which means that VP's ability to regulate AQP2 long-term has been impaired. This inability manifests as chronic, excessive thirst and urination, the hallmarks of NDI. In this case, CDI is accompanied by NDI.
In X-linked NDI, the most common form of inherited NDI, the vasopressin-2 receptor can't bind with VP; thus the kidneys can't concentrate urine to regulate water balance. In non-X-linked NDI, mutations in the AQP2 gene prevent AQP2 from performing its function. And again, cell membrane water permeability is markedly reduced and water balance suffers.
Acquired NDI has many causes, one of the most common being lithium use. In rats, repeated doses of lithium resulted in dramatic decreases in the level of AQP2 in the kidney and the ability for AQP2 to shuttle to the apex of the cell membranes. Thus, lithium effectively impairs both short and long-term regulation of cell water permeability. A condition known as hypokalemia is an electrolyte imbalance resulting from deficient potassium. Hypokalemia-induced NDI in rats is associated with a decrease in levels of AQP2 in the kidney, so only the long-term regulation of AQP2 by VP is impaired. Likewise, after bilateral ureteral obstruction (when both tubes that transfer urine from kidney to bladder are blocked) is repaired in rats, there are depleted amounts of AQP2 in the kidney. The long-term regulation of AQP2 by VP is impaired and the rats exhibit symptoms of NDI. It is noted that humans show symptoms of NDI as well after their bilateral ureteral obstructions are repaired.
Sometimes there can occur a sustained release of VP not linked to water-balancing needs. This can result in an over-stimulation of both short and long-term regulating mechanisms which leads to fluid retention and an excess of extracellular fluid volume. This is called syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH).
The authors concluded that understanding the workings of VP regulation of AQP2 is an important aid to further unraveling the molecular basis of the kidney's ability to balance water in the body.