Introduction
Aquaporins (AQP) are water-specific membrane proteins which determine membrane water permeability in many tissues. AQP1 is abundant in red blood cells, renal proximal tubule epithelium, pulmonary endothelium, and other sites. Demonstration of the Colton blood group antigen on AQP1 allowed identification of 6 Colton null kindreds worldwide; 3 of these kindreds have been evaluated and found to be AQP1 deficient. Surprisingly, all seemed to be phenotypically normal. We postulated that AQP1 null humans have subclinical defects in water transport that would become apparent under stress conditions.
Methods
We have evaluated two AQP1 null humans (JCCI approved protocols). Blood chemistry and hematology studies and renal function were determined at baseline. Serum and urine osmolality were measured over a 24-hour baseline period, as were vasopressin levels. Subjects were then water-deprived for up to 24 hours, and serum and urine osmolality and blood hormone levels were serially measured. Subjects were given oral lithium and water-loaded, and lithium and maximum water clearance were determined. We have also examined lung water transport in AQP1 null individuals. High resolution CT scan of the chest was performed and bronchiolar wall thickness was measured. They were then given 3 liters of intravenous saline, and high resolution CT scan was repeated after each liter. Bronchiolar wall thickness at baseline and after fluid challenge was determined.
Results
AQP1 null subjects had normal renal function and hematocrit, and no hemolysis. Kidney size and glomerular filtration rate were normal. With water deprivation, vasopressin levels increased in both subjects, however maximum urine concentration achieved by both AQP1 null subjects was 450 mosm/kg; this was not increased by exogenous vasopressin. One subject was given an infusion of hypertonic saline which increased serum osmolality from 289 to 304 mosm/kg, but urine osmolality did not increase. Control subjects exhibited urine osmolality greater than 800 mosm/kg after 10-12 water deprivation. Lithium clearance and maximal water clearance were normal. In the pulmonary evaluation, controls challenged with saline exhibited a 70% increase in bronchiolar wall thickness. In contrast, airway wall thickness did not change in AQP1 null subjects following fluid challenge.
Conclusions
These studies demonstrate that AQP1 null humans have alterations in renal and lung water transport that become apparent under stress conditions. AQP1 null individuals have a limited ability to concentrate urine in response to water deprivation. However, the normal maximal water clearance suggests the primary defect may not be in the proximal tubule, but rather further down the nephron. Additionally, water transport across the peribronchiolar vasculature was reduced in response to fluid challenge in the AQP1 null individuals. The pathophysiologic implications of this observation are at present unclear. These studies confirm a physiologic role for AQP1 in humans, and suggest that acquired changes in AQP1 expression or function may participate in a variety of pathophysiologic events.
References