Role of AQP1 in endotoxemia-induced acute kidney injury

1 Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; and 2 Department of Pathology, Dubrava University Hospital, Zagreb, Croatia Submitted 22 January 2008 ; accepted in final form 14 April 2008 The effect of endotoxemia (lipopolysaccharide, 2.5 mg/kg ip) was investigated in aquaporin (AQP) 1 knockout (KO) compared with wild-type (WT) mice. 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 urine osmolality was lower. The higher serum osmolality in AQP1-KO mice during endotoxemia was associated with higher AQP2 (133 ± 8 vs. 100 ± 3%, P < 0.01), AQP3 (140 ± 8 vs. 100 ± 4%, P < 0.001) and Na + -K + -2Cl – cotransporter type 2 (NKCC2; 152 ± 14 vs. 100 ± 15%, P < 0.05) expression than that in WT mice. These responses during endotoxemia in the AQP1-KO mice compared with WT were associated with lower glomerular filtration rate (GFR) (69 ± 8 vs. 96 ± 8 ml/min, P < 0.05) and renal blood flow (0.77 ± 0.1 vs. 1.01 ± 0.1 ml/min, P < 0.01). Urinary sodium excretion and fractional sodium excretion were higher in KO compared with WT mice in endotoxemia and were accompanied by more severe tubular injury. With water repletion and comparable serum osmolalities, GFR was still lower in KO (57 ± 13 vs. 120 ± 6 ml/min, P < 0.01) compared with WT during endotoxemia. The abundance of AQP2 and AQP3 protein in KO mice was not different from WT mice; however, NKCC2, Na + /H + exchanger type 3, 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 but rather absence of AQP1 predisposed to enhanced endotoximic renal injury. lipopolysaccharide; sepsis; glomerular filtration rate; polyuria; aquaporin-1 Address for reprint requests and other correspondence: R. W. Schrier, Division of Renal Diseases and Hypertension, Univ. of Colorado Health Sciences Center, 4200 East 9 th Ave., Box B173, Denver, CO 80262 (e-mail: Robert.Schrier{at}UCHSC.EDU )