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Epithelial cell polarity and hypoxia influence heme oxygenase-1 expression by heme in renal epithelial cells

Veterans Administration Medical Center and Departments of Medicine, Surgery, and Cell Biology, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 12 October 2005 ; accepted in final form 12 April 2006

Induction of heme oxygenase-1 (HO-1) in renal tubules occurs as an adaptive and beneficial response in acute renal failure (ARF) following ischemia and nephrotoxins. Using an in vitro model of polarized Madin-Darby canine kidney (MDCK) epithelial cells, we examined apical and basolateral cell surface sensitivity to HO-1 induction by heme. Basolateral exposure to 5 µM hemin (heme chloride) resulted in higher HO-1 induction than did apical exposure. The peak induction of HO-1 by basolateral application of hemin occurred between 12 and 18 h of exposure and was dose dependent. Similar cell surface sensitivity to hemin-induced HO-1 expression was observed using a mouse cortical collecting duct cell line (94D cells). Hepatocyte growth factor (HGF) is known to decrease cell polarity of MDCK cells. Following pretreatment with HGF, apically applied hemin gave greater stimulation of HO-1 expression, whereas HGF alone did not induce HO-1. We also examined the effect of hypoxia on hemin-mediated HO-1 induction. MDCK cells were subjected to hypoxia (1% O₂) for 24 h to simulate the effects of ischemic ARF. Under hypoxic conditions, both apical as well as basolateral surfaces of MDCK were more sensitive to HO-1 induction by hemin. Hypoxia alone did not induce HO-1 but appeared to potentiate both apical and basolateral sensitivity to hemin-mediated induction. These data demonstrate that the induction of HO-1 expression in polarized renal epithelia by heme is achieved primarily via basolateral exposure. However, under conditions of altered renal epithelial cell polarity and hypoxia, increased HO-1 induction occurs following apical exposure to heme.

acute renal failure; kidney; hepatocyte growth factor

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