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Protective Role of Hypoxia-Inducible Factor-2 against Ischemic Damage and Oxidative Stress in the Kidney

Ichiro Kojima^*, Tetsuhiro Tanaka^*, Reiko Inagi^*, Hideki Kato^*, Toshiharu Yamashita, Ai Sakiyama, Osamu Ohneda, Norihiko Takeda, Masataka Sata, Toshio Miyata, Toshiro Fujita^* and Masaomi Nangaku^*

^* Division of Nephrology and Endocrinology and Department of Cardiovascular Medicine, University of Tokyo School of Medicine, Tokyo, Department of Regenerative Medicine and Stem Cell Biology, University of Tsukuba, Tsukuba, and Institute of Medical Sciences, Tokai University School of Medicine, Kanagawa, Japan

Address correspondence to: Dr. Masaomi Nangaku, Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone:+81-3-3815-5411, ext. 33128; Fax:+81-3-5800-8806; E-mail: mnangaku-tky{at}umin.ac.jp.

Received for publication June 20, 2006. Accepted for publication January 26, 2007.

Central to cellular responses to hypoxic environment is the hypoxia-inducible factor (HIF) transcriptional control system. A role for HIF-2 was investigated in a model of renal ischemia-reperfusion injury (IRI) associated with oxidative stress using HIF-2 knockdown mice. In these mice, HIF-2 expression was approximately one half that of wild-type mice, whereas HIF-1 expression was equivalent. HIF-2 knockdown mice were more susceptible to renal IRI, as indicated by elevated blood urea nitrogen levels and semiquantitative histologic analysis. Immunostaining with markers of oxidative stress showed enhanced oxidative stress in the kidney of HIF-2 knockdown mice, which was associated with peritubular capillary loss. Real-time quantitative PCR analysis showed decreased expression of antioxidative stress genes in the HIF-2 knockdown kidneys. Studies that used small interference RNA confirmed regulation of the antioxidative stress genes in cultured endothelial cells. Although HIF-2 knockdown mice were anemic, serum erythropoietin levels were not significantly increased, reflecting inappropriate response to anemia as a result of HIF-2 knockdown. Experiments that used hemodiluted mice with renal ischemia demonstrated that anemia of this degree did not affect susceptibility to ischemia. Knockdown of HIF-2 in inflammatory cells by bone marrow transplantation experiments demonstrated that HIF-2 in inflammatory cells did not contribute to susceptibility to renal IRI. Restoration of HIF-2 in endothelium by intercrossing with Tie1-Cre mice ameliorated renal injury by IRI, demonstrating a specific role of endothelial HIF-2. These results suggest that HIF-2 in the endothelium has a protective role against ischemia of the kidney via amelioration of oxidative stress.

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