SEVERELY IMPAIRED URINARY CONCENTRATING ABILITY IN TRANSGENIC MICE LACKING AQUAPORIN-1 WATER CHANNELS

Water channel aquaporin-1 (AQP1) is strongly ex pressed in kidney in p roximal tubule and descending limb of Henle epithelia and, in vasa rec ta endothelia, The grossly normal phenotype in human subjects deficien t in AQP1 (Colton null blood group) and in AQP4 knockout mice has sugg ested that aquaporins (other than the vasopressin-regulated water chan nel AQP2) may not be important in mammalian physiology, We have genera ted transgenic mice lacking detectable AQP1. by targeted gene disrupti on, In kidney proximal tubule membrane vesicles from knockout mice, os motic water permeability was reduced 8-fold compared with vesicles fro m wild-type mice, Although the knockout mice were grossly normal In te rms of survival, physical appearance, and organ morphology, they becam e severely dehydrated and lethargic after water deprivation for 36 h, Body weight decreased by 35 +/- 2%, serum osmolality increased to >500 mOsm, and urinary osmolality (657 +/- 59 mOsm) did not change from th at before water deprivation. In contrast, wild-type and heterozygous m ice remained active after water deprivation, body weight decreased by 20-22%, serum osmolality remained normal (810-330 mOsm), and urine osm olality rose to >2500 mOsm, Urine [Na+] in water-deprived knockout mic e was <10 mM, and urine osmolality was slot increased by the V2 agonis t DDAVP, The results suggest that AQP1 knockout mice are unable to cre ate a hypertonic medullary interstitium by countercurrent multiplicati on, AQP1 is thus required for the formation of a concentrated urine by the kidney.