The water channel, aquaporin-1 (AQP1) is the principal water pathway for isotonic water reabsorption in the kidney proximal tubule (PT). We investigated flow-mediated fluid (Jv) and HCO3- (JHCO3) reabsorption in proximal tubules of mouse kidney by microperfusion in wild-type (WT) and AQP1-KO mice. The experiments were simulated in an adaptation of a mathematical model of rat PT. An increase in perfusion rate from 5 to 20 nl/min increased Jv and JHCO3 in PTs of WT mice. AQP1-KO significantly decreased Jv at low and high flow rates compared with control. In contrast, the JHCO3 was not reduced at either low or high flow rates. Cell volume showed no significant difference between WT and AQP1-KO mice. Renal clearance experiments showed significantly higher urine flow in AQP1-KO mouse but there was no significant difference in either Na+ and K+ or HCO3- excretion. The acid-base parameters of blood pH, PCO2, HCO3-and urine pH were the same in both WT and KO. In model calculations, tubules whose tight junction (TJ) Pf was that assigned to rat TJ, showed no difference in Jv between WT and KO; whereas TJ Pf set to 25% of rat, predicted Jvconcordant with our observations from AQP1-KO. These results affirm the dominance of AQP1 in mediating isotonic water reabsorption by mouse PT and demonstrate that flow-stimulated HCO3- reabsorption is intact and independent of AQP1. With reference to the model, the findings also suggest that tight junctional water flux in PT is less prominent in mouse than in rat kidney.