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Am J Physiol Renal Physiol 289: F1123-F1133, 2005. First published June 14, 2005; doi:10.1152/ajprenal.00081.2005
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Hypoxia-inducible factor modulates tubular cell survival in cisplatin nephrotoxicity

Tetsuhiro Tanaka,1 Ichiro Kojima,1 Takamoto Ohse,1 Reiko Inagi,2 Toshio Miyata,2 Julie R. Ingelfinger,3 Toshiro Fujita,1 and Masaomi Nangaku1

1Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo; 2Institute of Medical Sciences, Tokai University, Kanagawa, Japan; and 3Division of Pediatric Nephrology, Massachusetts General Hospital, Boston, Massachusetts

Submitted 28 February 2005 ; accepted in final form 10 June 2005

Hypoxia-inducible factor (HIF)-1 is a transcription factor mediating cellular response to hypoxia. Although it is expressed in tubular cells of the ischemic kidney, its functional role is not fully clarified in the pathological context. In this study, we investigated a role of HIF in tubular cell apoptosis induced by cisplatin. HIF-1{alpha} was expressed in tubular cells in the outer medulla 3 days after cisplatin (6 mg/kg) administration. With the in vivo administration of cobalt to activate HIF, the number of apoptotic renal tubular cells became much smaller in the outer medulla, compared with the vehicle group. We also examined the functional role of HIF-1 in vitro using immortalized rat proximal tubular cells (IRPTC). In hypoxia, IRPTC that express dominant-negative (dn) HIF-1{alpha} showed impaired survival in cisplatin injury at variable doses (25–100 µM, 24 h), which was not obvious in normoxia. The observed difference in cell viability in hypoxia was associated with the increased number of apoptotic cells in dnHIF-1{alpha} clones (Hoechst 33258 staining). Studies on intracellular signaling revealed that the degree of cytochrome c release, dissipation of mitochondrial membrane potentials, and caspase-9 activity were all more prominent in dnHIF-1{alpha} clones than in control IRPTC, pointing to the accelerated signaling of mitochondrial pathways. We propose that HIF-1 mediates cytoprotection against cisplatin injury in hypoxic renal tubular cells, by reducing the number of apoptotic cells through stabilization of mitochondrial membrane integrity and suppression of apoptosis signaling. A possibility was suggested that activation of HIF-1 could be a new promising therapeutic target for hypoxic renal diseases.

apoptosis; mitochondria; caspase


Address for reprint requests and other correspondence: M. Nangaku, Division of Nephrology and Endocrinology, Univ. of Tokyo School of Medicine, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan (e-mail: mnangaku-tky{at}umin.ac.jp)




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