Role of Water Channels in Kidney and Lung

Aquaporins (AQPs) are membrane proteins that function as water channels facilitating a rapid and regulated transport of water across cell membranes. AQPs in kidney and lung play pivotal roles for the regulation of water homeostasis. In this thesis, I addressed questions concerning functional significance of AQPs in the kidney and lung, with particular emphasis on the role of AQPs in pathophysiological conditions related to an impaired water balance during postnatal adaptation. We assessed urinary AQP2 level in preterm and term infants during the postnatal period. We could demonstrate that urinary AQP2 correlates with the overall maturity of tubular function in human neonates. Urinary AQP2 may reflect AQP2 expression level associated with different physiological and pathophysiological conditions. We further investigated whether AQP2 plays a role in water balance disturbances in preterm infants treated with prostaglandin inhibitors for patent ductus arteriosus closure. Urinary AQP2 level, along with urinary osmolality, was significantly decreased during both ibuprofen and indomethacin treatment. The overall low urinary osmolality and the dissociation between urinary osmolality and urinary AQP2 level indicate that AQP2 may not be a factor contributing to the fluid retention sometimes observed in infants with patent ductus arteriosus treated with prostaglandin inhibitors. To investigate whether AQP4 may play a role in renal K transport, we performed a series of experimental studies and developed a mathematical model, indicating that AQP4, Na, K-ATPase and inwardly rectifying K channel Kir7.1 form a transporting microdomain, where AQP4 may play a modulating role for K transport across the basolateral membrane of the principal cell by maintaining a local extracellular K concentration that is favorable for K recirculation across the basal membrane, and thus for the activity of Na, K-ATPase and K secretion. We also study the role of AQPs and ion transporters in pathophysiological conditions related to delayed clearance of fetal lung fluid. We have found that the neonatal respiratory distress is associated with changes in β-ENaC and AQP5 expression. The lower β-ENaC expression may be one of the factors that predispose to the development of respiratory distress syndrome in the newborn infants. The higher AQP5 expression may provide the possibility for reabsorption of postnatal lung liquid, which contributes to quick recovery of infants with transient tachypnea of the newborn. In conclusion, this thesis presents novel data about AQPs in the immature kidney and lung during the early postnatal period and demonstrates the crucial role of AQPs for postnatal adaptation in infants, especially in premature infants. Alterations in the expression of water and ion transportors in infants is associated with pathophysiological conditions related to impaired renal regulation of fluid and electrolyte balance, as well as delayed clearance of lung fluid. Furthermore, AQP4 expressed in the kidney may not only be important for water transport, but also be involved in renal K transport. LIST OF PUBLICATIONS I. Zelenina M, Li Y, Glorieux I, Arnaud C, Cristini C, Decramer S, Aperia A, Casper C. Urinary aquaporin-2 excretion during early human development. Pediatric Nephrology 21: 947–952, 2006. II. LI Y, Plat-Willson G, Marcoux MO, Zelenina M, Aperia A, Casper C. Urinary aquaporin-2 excretion during ibuprofen or indomethacin treatment in preterm infants with patent ductus arteriosus. Manuscript. III. Zelenina M, LI Y, Kamali-Zare P, Sakuraba S, MacAulay N, Zelenin S, Bondar A, Brismar H, Aperia A. A role for AQP4 in renal K transport. Manuscript. IV. Li Y, Marcoux MO, Gineste M, Vanpee M, Zelenina M, Casper C. Expression of water and ion transporters in tracheal aspirates from neonates with respiratory distress. Acta Paediatrica, 98 (11): 1729-37, 2009.