1999 European Regional Conference Proceeding

May 12 - 16, 1999

Conference: 1999 European Regional Conference
Title: Long-term regulation of aquaporin-2: a possible therapeutic approach to NDI?
Author: Marples, David
Institution: University of Leeds
David Marples The renal collecting duct is responsible for the control of body water balance. This is achieved by increasing collecting duct water permeability in response to the antidiuretic hormone vasopressin, thus allowing the reabsorption of water from the tubular fluid, and the production of a concentrated urine. The process depends on the delivery of water channels (aquaporin-2, or AQP2) from a store in vesicles within the cell to the apical plasma membrane. This exocytic delivery is triggered by vasopressin binding to its receptors on the basolateral membrane. Nephrogenic diabetes insipidus (NDI) occurs because of a breakdown in this process, either because the cells are unable to respond to vasopressin, or because functional AQP2 is not available to insert into the plasma membrane. It has long been known that the kidney can increase or decrease its responsiveness to vasopressin in both physiological and pathological ways. More recently, it has become clear that one aspect of this adaptation is a change in the expression of AQP2. In a number of forms of acquired NDI the levels of AQP2 are greatly reduced, probably contributing to the increased urine production. Decreased AQP2 expression is also seen in hereditary forms of NDI, where it probably compounds the primary defect. Taken together, these studies have demonstrated that AQP2 expression is controlled by both vasopressin - dependent and - independent pathways. We are seeking to understand the pathways involved in this regulation of expression, and much of our interest is currently focused on the role of prostaglandins, which seem to have a stimulatory effect. If we can activate pathways that increase AQP2 expression, this may provide a useful approach to treating many acquired forms of NDI, and may also alleviate the polyuria seen in some forms of hereditary NDI.

The kidney collecting ducts are responsible for helping control the body's water balance. They do this by allowing the kidney to reabsorb much of the body water that flows through them. The kidneys are able to reabsorb the body water flowing through the collecting ducts when a protein called aquaporin-2 (AQP2) is inserted into the apical membrane of the principal cells that line the collecting ducts. AQP2s then act as channels through which much greater amounts of body water can pass into the kidney than when AQP2s are not present in the apical membranes.

The signal that sends the AQP2s to the apical membranes occurs when the antidiuretic hormone, vasopressin (VP), binds to the vasopressin-2 receptor, located in the basolateral membrane of the collecting duct principal cells. In nephrogenic diabetes insipidus (NDI), AQP2s are unable to perform their water channeling function. Because of this, the kidneys cannot reabsorb the body water flowing through the collecting ducts and the unabsorbed water leaves the body as excessive urine.

NDI can either be inherited or acquired, and in both cases the number of AQP2s that are expressed in the collecting duct principal cells are reduced. Studies have demonstrated that the number of AQP2s that are expressed in these cells can be controlled by molecular pathways that are both dependent on and independent of VP binding with its V2 receptors. Research is now focused on acquiring a deeper understanding of the different molecular pathways involved in AQP2 expression. Marples suggests that if researchers learn how to activate molecular pathways that increase the number of AQP2s in the principal cells, they may be able to develop treatments for many of the acquired forms of NDI. These treatments might also help reduce the excessive urination associated with some hereditary forms of NDI. One possible approach might be to stimulate the production of prostaglandins, molecules often associated with inflammation, but which seem to increase production of AQP2 in the kidney.