Role of aquaporins in renal water handling: physiology and pathophysiology.

the six bilayer spanning domains are connected by five Introduction loops (A–E in Figure 1). The molecule consists of two repeats of three a-helices which are 180° mirror images An essential function of the mammalian kidney is its of each other (Figure 1). Each repeat contains the ability to conserve or excrete free water independent highly conserved family characteristic asparagineof changes in solute excretion. Early physiological proline-alanine (NPA) sequence in loops B and E. studies have provided evidence for constitutive absorpLoops B and E are postulated to fold back into the tion of about 90% of the GFR volume in proximal membrane and form the water pore. Recently, the threetubules and descending limbs of Henle’s loop, whereas dimensional structure of AQP1 was determined at 6Å facultative water reabsorption occurs in collecting resolution by cryo-electron crystallography [8]. AQP1 ducts under control of the antidiuretic hormone arginis a homotetramer containing four independent aqueous ine vasopressin (AVP). Although all cell membranes channels. It was shown that each monomer is composed have a surpringly high diffusive water permeability, it of six tilted a-helices which form a barrel that encloses is now clear that water transport in the nephron is a central density which is attributed to the functionally facilitated by water channels [1]. important NPA boxes in loops B and E. Given the Discovery of the aquaporin family of water channels highly homologues primary structures of AQP1 and the has provided insight in the molecular mechanisms by other aquaporins, it is likely that all AQPs have a more which rapid osmotic water flow occurs in kidney and or less similar three-dimensional structure. The less in other organs. Nine mammalian aquaporins, AQPs, conserved region among the aquaporins is the carboxyhave been cloned to date, of which AQP1, 2, 3, 4, 6, terminus and this property has been exploited to gener7 are expressed in kidney (for review see [1–3], new ate highly specific polyclonal antibodies which have aquaporins [4–6 ]). Aquaporins belong to an old ubibeen very useful for localization studies. quitous major intrinsic protein (MIP) family of transmembrane channel proteins of which at present close Aquaporin 0/MIP to hundred members have been identified [7]. The evolutionary history suggests that all current MIP family proteins have derived from two divergent bacThe major intrinsic protein (MIP) is a 26-kDa protein terial paralogues, one a glycerol facilitator which is which is exclusively expressed in lens fibre cells in impermeable for water and the other an aquaporin which is impermeable for glycerol [7]. Two mammalian aquaporins, AQP3 and 7, are permeable for water and glycerol, but all other AQPs are selective for water [1,5]. In this review we will bring together recent insight into the role of aquaporins in renal water handling and in water balance disorders.