DISCOVERY OF AQUAPORINS - A BREAKTHROUGH IN RESEARCH ON RENAL WATER TRANSPORT

Several membranes of the kidney are highly water permeable, thereby en abling this organ to retain large quantities of water. Recently, the m olecular identification of water channels responsible for this high wa ter permeability has finally been accomplished. At present, four disti nct renal water channels have been identified, all members of the fami ly 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 puta tive renal water channel (WCH3) has been found. AQP1 is expressed in a pical and basolateral membranes of proximal tubules and descending lim bs of Henle, AQP2 predominantly in apical membranes of principal and i nner medullary collecting duct cells and AQP3 in basolateral membranes of kidney collecting duct cells. MIWC is expressed in the inner medul la of the kidney and has been suggested to be localised in the vasa re cta. The human genes encoding AQP1 and AQP2 have been cloned, permitti ng deduction of their amino acid sequence, prediction of their two-dim ensional structure by hydropathy analysis, speculations on their way o f functioning and DNA analysis in patients with diseases possibly caus ed by mutant aquaporins. Mutations in the AQP1 gene were recently dete cted 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 insipidu s. The renal unresponsiveness to arginine vasopressin, which character ises this disease, is in accordance with the assumption that AQP2 is t he effector protein of the renal vasopressin pathway. The influence of amino acid substitutions on the functioning of AQP1 and 2 was demonst rated by in vitro expression studies in oocytes of the toad Xenopus la evis. Future research on renal water transport will focus on the searc h for other aquaporins, structure-function relationship of aquaporins, the development of aquaporin inhibitors and their possible use as diu retics, and further elucidation of the renal vasopressin pathway.