Discovery of Aquaporins: a Breakthrough in Research on Renal Water Transport

Title: Discovery of Aquaporins: a Breakthrough in Research on Renal Water Transport
Authors: van Lieburg, Angenita; Knoers, Nine; Deen, Peter M.T.
Publisher: Pediatric Nephrology
Date Published: April 01, 1995
Reference Number: 74
Several membranes of the kidney are highly water permeable, thereby enabling this organ to retain large quantities of water. Recently, the molecular identification of water channels responsible for this high water permeability has finally been accomplished. At present, four distinct renal water channels have been identified, all members of the family of major intrinsic proteins. Aquaporin 1 (AQP1), aquaporin 2 (AQP2) and the mercury-insensitive water channel (MIWC) are water-selective channel proteins, whereas the fourth, referred to as aquaporin 3 (AQP3), permits transport of urea and glycerol as well. Furthermore, a putative renal water channel (WCH3) has been found. AQP1 is expressed in apical and basolateral membranes of proximal tubules and descending limbs of Henle, AQP2 predominantly in apical membranes of principal and inner medullary collecting duct cells and AQP3 in basolateral membranes of kidney collecting duct cells. MIWC is expressed in the inner medulla of the kidney and has been suggested to be localised in the vasa recta. The human genes encoding AQP1 and AQP2 have been cloned, permitting deduction of their amino acid sequence, prediction of their two-dimensional structure by hydropathy analysis, speculations on their way of functioning and DNA analysis in patients with diseases possibly caused by mutant aquaporins. Mutations in the AQP1 gene were recently detected in clinically normal individuals, a finding which contradicts the presumed vital importance of this protein. Mutations in the AQP2 gene were shown to cause autosomal recessive nephrogenic diabetes insipidus. The renal unresponsiveness to arginine vasopressin, which characterises this disease, is in accordance with the assumption that AQP2 is the effector protein of the renal vasopressin pathway.

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)

The family of water-transporting proteins called aquaporins are the molecular basis of the kidney's ability to maintain body water balance through reabsorbing water. Aquaporins insert themselves in specific cell membranes in order to allow much more water than usual to pass through these membranes.

The nephron is the main working unit of the kidney. There are about a million of them in each kidney. Each nephron consists of a filtering unit called a glomerulus and a small tube called a tubule. The tubule has different sections. The section nearest the glomerulus is called the proximal tubule, and the section furthest from the glomerulus is called the distal tubule. In-between these is a section called the loop of Henle, which has ascending and descending limbs. The distal tubule runs into a kidney collecting duct. The proximal tubules and the descending limbs of Henle reabsorb about 90% of the body water that flows through the glomeruli. Reabsorption of differing amounts of the remaining water occurs through the collecting ducts. The reabsorption in the collecting ducts is regulated by the antidiuretic hormone, arginine vasopressin (AVP), and accomplished by a member of the aquaporin family, aquaporin-2 (AQP2), that is located in the principal cells of the collecting duct.

When signaled to do so by a molecular sequence initiated by AVP, AQP2s shuttle from their holding place inside the cell to the cell membrane. When AQP2s insert themselves in the cell membranes, they increase the water flow through the cell. Then, when signaled, they shuttle out of the membrane back to their holding places inside the cell.

To imagine the structure of the AQP2 picture a beaded string (the beads are amino acids). Most of the string lies in six folded clumps called transmembrane domains (or helices or regions) inside the cell membrane, the thin strip encircling the cell separating the inside of the cell from the outside. Part of the AQP2 snakes outside the cell forming three curves called extracellular loops A, C and E. Part of it snakes inside the cell forming two curves called intracellular loops B and D. Both ends of the AQP2 are inside the cell along with the intracellular loops. Researchers think that loop B meets loop E halfway across the membrane to form a narrow channel through which water can pass. (You can look at a diagram of an AQP2 for a clearer understanding.)

Mutations in AQP2 genes produce AQP2s which have structural differences from the normal AQP2. These structural differences affect the AQP2s ability to function. Dysfunctional AQP2s are one cause of nephrogenic diabetes insipidus (NDI), a disease marked by polyuria (chronic, excessive passage of large amounts of dilute urine) and polydipsia (chronic, excessive thirst.) NDI is characterized by the inability of the kidney to respond to the antidiuretic action of the molecular sequence initiated when AVP binds with its receptor, the vasopressin-2 receptor (V2R).

van Lieburg, et al., proved that functional defects of AQP2s synthesized by mutant AQP2 genes prevented AQP2s from transporting water through cell membranes by expressing clones of mutated AQP2 genes in laboratory cell cultures and measuring the ability of the resultant AQP2s to transport water. They found that defective AQP2s were non-functional. When the authors expressed defective AQP2s along with normal AQP2s, the normal AQP2s' ability to function was not impaired by the defective AQP2s.