Aquaporin-3 deletion in mice results in renal collecting duct abnormalities and worsens ischemia-reperfusion injury.
Aquaporin-3 (AQP3), a transporter of water, glycerol and H2O2, is expressed in basolateral membranes of principal cells in kidney collecting duct. Here, we report that AQP3 deletion in mice affects renal function and modulates renal injury. We found collecting duct hyperplasia and cell swelling in kidneys of adult AQP3 null mice. After mild renal ischemia-reperfusion (IR), AQP3 null mice had significantly greater blood urea nitrogen (57mg/dl) and creatinine (136μM) than wild-type mice (35mg/dl and 48μM, respectively), and showed renal morphological changes, including tubular dilatation, erythrocyte diapedesis and collecting duct incompletion. MPO, MDA and SOD following IR in AQP3 null mice were significantly different from that in wild-type mice (1.7U/g vs 0.8U/g, 3.9μM/g vs 2.4μM/g, 6.4U/mg vs 11U/mg, respectively). Following IR, AQP3 deletion inhibited activation of mitogen-activated protein kinase (MAPK) signaling and produced an increase in the ratios of Bax/Bcl-2, cleaved caspase-3/caspase-3 and p-p53/p53. Studies in transfected MDCK cells showed that AQP3 expression attenuated reduced cell viability following hypoxia-reoxygenation, with reduced apoptosis and increased MAPK signaling. Our results support a novel role for AQP3 in modulating renal injury and suggest the mechanisms involved in protection against hypoxic injury.
Department of Pharmacology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Natural and Biomimetic Drugs, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Lei
L
Lei
Department of Pharmacology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Natural and Biomimetic Drugs, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Weiling
W
Wang
Department of Pharmacology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Natural and Biomimetic Drugs, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Yingli
Y
Jia
Department of Pharmacology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Natural and Biomimetic Drugs, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Limin
L
Su
Department of Pharmacology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Natural and Biomimetic Drugs, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China.
Hong
H
Zhou
Departments of Medicine and Physiology, University of California San Francisco, CA 94143, USA.
Alan S
AS
Verkman
Department of Pharmacology, School of Basic Medical Sciences, Peking University, State Key Laboratory of Natural and Biomimetic Drugs, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing 100191, China. Electronic address: baoxue@bjmu.edu.cn.
Baoxue
B
Yang
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D051400:Aquaporin 3 / Q000172:deficiency*; D017353:Gene Deletion; D007674:Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007685:Kidney Tubules, Collecting / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008817:Mice, Mutant Strains; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
D051017:Apoptosis Regulatory Proteins; C496028:Aqp3 protein, mouse; D051400:Aquaporin 3
AQP3; Acute kidney injury; Ischemic injury; Kidney; MAPK; MDCK