1998 Global Conference Proceeding

March 02 - 04, 1998

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Conference: 1998 Global Conference
Title: Decreased Aquaporin-2 Water Channel Expression in Acquired Nephrogenic Diabetes Insipidus
Author: Marples, David
Institution: University of Leeds
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Abstract • Translation

The most common forms of nephrogenic diabetes insipidus (NDI) are those that arise secondary to other disorders or treatments. While rarely as severe as the hereditary forms of the disease, acquired NDI is a major source of morbidity. About 1 American in 1000 is undergoing lithium treatment, the commonest cause of acquired NDI, and 20 - 30% of these have clinically significant polyuria as a consequence. Post-obstructive diuresis and electrolyte disturbances secondary to diuretic treatment (hypokalemia) or cancer (hypercalcemia) are also common causes of NDI.

We have shown in a series of recent studies that expression of aquaporin-2 (AQP2), the vasopressin-regulated water channel of the kidney collecting duct, is greatly reduced after experimental induction of these common acquired forms of NDI in rats. In some of these conditions there is also impaired delivery of these channels to the apical plasma membrane, where they permit water reabsorption from the urine. The combination of these factors is likely to underlie the urinary concentrating defect that defines these conditions.

Direct infusion of vasopressin in rats causes an increase in AQP2 expression, probably via a rise in cytosolic cAMP (which also acts as the second messenger triggering the delivery of AQP2 to the plasma membrane). However, it is clear from the studies to be described that there are also vasopressin-independent pathways that regulate the expression of AQP2, some of which appear to reflect intra-nephric changes, while others involve systemic signals. We are currently searching for these signals, with the ultimate aim of correcting the defects.

These studies also show that recovery of AQP2 expression, even after correction of the underlying condition, can be slow, consistent with the clinical observation that recovery of urinary concentrating ability often takes weeks or months. An understanding of the cellular signals and mechanisms responsible for the decrease in AQP2 expression may make it possible to develop treatments for this common clinical problem.

Acquired nephrogenic diabetes insipidus (NDI) is more common than congenital NDI, though rarely as severe. A water-transporting protein called aquaporin-2 (AQP2) plays an important role in promoting water reabsorption in the kidneys and thus helps in regulating urine production. In rats in which acquired NDI has been induced, the amount of AQP2 is greatly reduced. In some forms of acquired NDI the protein also functioned less well. When the rats got a continuous infusion of the antidiuretic hormone, vasopressin, the AQP2 was more capable of doing its job. There was some increase in the amount of AQP2, but the studies also make clear that there are cellular pathways not depending on vasopressin which can alter the amount of AQP2. Some of these pathways appear to reflect changes within the kidney, and others involve some type of biochemical signals. The authors' studies also have shown that even after the conditions causing acquired NDI have been corrected it still takes a while for AQP2 to return to normal function. They hope their research will lead to alleviation of the defects in kidney function and the problems they cause.