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J. Biol. Chem., Vol. 281, Issue 23, 15687-15693, June 9, 2006

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Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes^*

Maria Antonietta Di Noia¹, Sarah Van Driesche¹, Ferdinando Palmieri², Li-Ming Yang, Shuo Quan, Alvin I. Goodman, and Nader G. Abraham³

From the Department of Pharmaco-Biology, University of Bari, 70125 Bari, Italy and the Department of Pharmacology and Medicine, New York Medical College, Valhalla, New York 10595

Up-regulation of heme oxygenase (HO-1) by either cobalt protoporphyrin (CoPP) or human gene transfer improves vascular and renal function by several mechanisms, including increases in antioxidant levels and decreases in reactive oxygen species (ROS) in vascular and renal tissue. The purpose of the present study was to determine the effect of HO-1 overexpression on mitochondrial transporters, cytochrome c oxidase, and anti-apoptotic proteins in diabetic rats (streptozotocin, (STZ)-induced type 1 diabetes). Renal mitochondrial carnitine, deoxynucleotide, and ADP/ATP carriers were significantly reduced in diabetic compared with nondiabetic rats (p < 0.05). The citrate carrier was not significantly decreased in diabetic tissue. CoPP administration produced a robust increase in carnitine, citrate, deoxynucleotide, dicarboxylate, and ADP/ATP carriers and no significant change in oxoglutarate and aspartate/glutamate carriers. The increase in mitochondrial carriers (MCs) was associated with a significant increase in cytochrome c oxidase activity. The administration of tin mesoporphyrin (SnMP), an inhibitor of HO-1 activity, prevented the restoration of MCs in diabetic rats. Human HO-1 cDNA transfer into diabetic rats increased both HO-1 protein and activity, and restored mitochondrial ADP/ATP and deoxynucleotide carriers. The increase in HO-1 by CoPP administration was associated with a significant increase in the phosphorylation of AKT and levels of BcL-XL proteins. These observations in experimental diabetes suggest that the cytoprotective mechanism of HO-1 against oxidative stress involves an increase in the levels of MCs and anti-apoptotic proteins as well as in cytochrome c oxidase activity.

Received for publication, September 27, 2005 , and in revised form, March 27, 2006.

^* This work was supported by National Institutes of Health Grants HL55601 and HL34300, by Philip Morris USA, Inc. and Philip Morris International (NGA), grants from MIUR, CEGBA, and the EC contract LSHM-C T-2004-503116. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally.

² To whom correspondence may be addressed: Dipartimento Farmaco-Biologico, Universita' di Bari, Via E. Orabona 4, 70125 BARI, Italy. Tel.: 39-80-5443374-5443323; Fax: 39-80-5442770; E-mail: fpalm{at}farmbiol.uniba.it. ³ To whom correspondence may be addressed: NY Medical College, Valhalla, NY 10595. Tel.: 914-594-4132; Fax: 914-594-4119; E-mail: nader_abraham{at}nymc.edu.

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