DEFECTIVE PROXIMAL TUBULAR FLUID REABSORPTION IN TRANSGENIC AQUAPORIN-1 NULL MICE

To investigate the role of aquaporin-l (AQP1) water channels in proxim al tubule function, in vitro proximal tubule microperfusion and in viv o micropuncture measurements were done on AQP1 knockout mice. The knoc k-out mice were generated by targeted gene disruption and found previo usly to be unable to concentrate their urine in response to water depr ivation, Unanesthetized knockout mice consumed 2.8-fold more fluid tha n wild-type mice and had lower urine osmolality (505 +/- 40 vs. 1081 /- 68 milliosmolar). Transepithelial osmotic water permeability (Pf) i n isolated microperfused S2 segments of proximal tubule from AQP1 knoc kout [-/-] mice was 0.033 +/- 0.005 cm/s (SE, it = 6 mice, 37 degrees C), much lower than that of 0.15 +/- 0.03 cm/s (n = 8) in tubules from wild-type [ +/+] mice (P < 0.01). In the presence of isosmolar lumina l perfusate and bath solutions, spontaneous fluid absorption rates (nl /min/mm tubule length) were 0.31 +/- 0.12 (-/-, it = 5) and 0.64 +/- 0 .15 (+/+, n = 8), As determined by free-flow micropuncture, the ratios of tubular fluid-to-plasma concentrations of an impermeant marker TF/ P in end proximal tubule fluid were 1.36 +/- 0.05 (-/-, rt 8 mice [53 tubules]) and 1.95 +/- 0.09 (+/+, n = 7 mice [40 tubules]) (P < 0.001) , corresponding to 26 +/- 3% [-/-] and 48 +/- 2% [+/+] absorption of t he filtered fluid load, In collections of distal tubule fluid, TF/P me re 2.8 +/- 0.3 [-/-] and 4.4 +/- 0.5 [+/+], corresponding to 62 +/- 4% [-/-] and 76 +/- 3% [+/+] absorption (P < 0.02), These data indicate that AQP1 deletion in mice results in decreased transepithelial proxim al tubule water permeability and defective fluid absorption. Thus, the high water permeability in proximal tubule of wild-type mice is prima rily transcellular, mediated by AQP1 mater channels, and required for efficient near-isosmolar fluid absorption.