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1 Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, Tokyo, Japan
2 Institute of Medical Sciences, Tokai University, Kanagawa, Japan
3 Division of Pediatric Nephrology, Massachusetts General Hospital, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: mnangaku-tky{at}umin.ac.jp.
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. Here we investigated a
role of HIF in tubular cell apoptosis induced by cisplatin. HIF-1
was expressed in
tubular cells in the outer medulla 3 days after cisplatin (6mg/kg) administration. By the
in vivo administration of cobalt to activate HIF, the number of apoptotic renal tubular
cells became much smaller in the outer medulla, as compared to the vehicle group. Then,
the functional role of HIF-1 was examined in vitro using immortalized rat proximal
tubular cells (IRPTC). In hypoxia, IRPTC that express dominant-negative (dn) HIF-1
showed impaired survival in cisplatin injury at variable doses (25-100µM, 24 h), which
was not obvious in normoxia. The observed difference in cell viability in hypoxia was
associated with the increased number of apoptosis in dnHIF-1 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 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 apoptosis 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.
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