The year of the pores

Abstract

Molecular biology has dominated the scene in nephrology in 1996, substantially advancing our understanding of physiology and pathophysiology. Take the aquaporin water channels (I~ng). Water transport across cellular membranes has always puzzled physiologists, since it appeared that water permeability could not be explained only by diffusion through the lipid bilayer. The existence of membrane water channels was shown by the discovery of aquaporin 1 (AQP1), initially called CHIP 28 (channel-forming integral protein of 28 kDa), in red blood cell membranes. Since then, five other structurally related proteins have been identified and named aquaporin-0 to aquaporin-5 (ff Nephrol 1996; 9: 58). Soon after its discovery, AQP1 was shown to be highly expressed in renal proximal convoluted tubules and in the descending limb of the loop of Henle, where 50-60% of filtered solute and water are reabsorbed. Immunoelectronmicroscopy showed that AQP1 localises in apical and basolateral plasma membranes, which act as entrance and exit routes for transepithelial water (figure). According to northern-blot analysis, AQP1 is widely distributed in several organ systems, so it is surprising that the few individuals so far identified for mutation of the AQP1 gene have no obvious clinical abnormalities. AQP2 is only expressed by the kidney medulla. AQP2, which is expressed only by the renal medulla, is unregulated by dehydration and by arginine vasopressin (Bai). Patients with autosomal recessive nephrogenic diabetes insipidus have a mutation in the AQP2 gene that encodes a non-funct ioning protein (Knoers). Abnormalities of AQP2 expression may also cause water retention. Messenger RNA expression of AQP2 studied in kidneys of rats with experimental liver cirrhosis was significantly higher than in kidneys of normal rats and correlated significantly with the volume of ascites (Hepatology 1995; 21: 169). At the meeting of the American Society of Nephrology it was reported that AQP2 expression is increased in normal pregnancy. Schrier measured serially AQP2 mRNA expression in pregnant rats, and found that it was increased in the whole kidney and specially in the papilla, and that mRNA expression progressively increased as pregnancy advanced (ff Am Soc Nephrol 1996; 7: 1274). Another area of research is cystic diseases of the kidney. Autosomal dominant polycystic kidney disease (APKD) accounts for about 8% of cases of end-stage renal disease. At the moment no treatment is available to arrest cyst formation and growth. The defective gene, which has been named PKD1, is located on chromosome 16p. In APKD, the early stages of cysts are characterised by dedifferentiation of cystic epithelia and abnormalities of the basement membrane. PKD1 encodes a 4302-