The effect of endotoxemia (LPS 2.5mg/kg, i.p) was investigated in AQP1 knockout (KO) as compared to wild type mice (WT). At baseline KO mice exhibited higher water intake (WI) and urine output (UO). After endotoxemia WI and UO remained higher in the KO than WT mice and Uosm was lower. The higher serum omolality in AQP1-KO mice during endotoxemia were associated with higher AQP2 (133 ± 8% vs. 100 ± 3%, p<0.01), AQP3 (140 ± 8% vs. 100 ± 4%, p<0.001) and NKCC2 (152 ± 14% vs. 100 ± 15%, p<0.05) expression than that in WT mice. These responses during endotoxemia in the AQP1-KO mice as compared to WT were associated with lower GFR (69 ± 8 vs. 96 ± 8ml/min, p<0.05) and renal blood flow (0.77 ± 0.1 vs. 1.01 ± 0.1ml/min, p<0.01). Urinary sodium excretion and fractional sodium excretion were higher in KO compared with WT mice in endotoxemia and was accompanied by more severe tubular injury. With water repletion and comparable serum osmolalities, GFR was still lower in KO (57 ± 13 vs. 120 ± 6ml/min, p<0.01) as compared with WT during endotoxemia. The abundance of AQP2 and AQP3 protein in KO mice was not different from WT mice, however, NKCC2, NHE3 and fractional sodium excretion remained higher in KO compared with WT. Thus the polyuria in AQP1-KO mice does not protect against endotoxemia induced acute kidney injury, rather absence of AQP1 predisposed to enhanced endotoximic renal injury.