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J. Biol. Chem., Vol. 279, Issue 1, 765-771, January 2, 2004

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Metallothionein Protects Islets from Hypoxia and Extends Islet Graft Survival by Scavenging Most Kinds of Reactive Oxygen Species^*

Xiaoyan Li, Hainan Chen, and Paul N. Epstein¶||

From the Departments of Pharmacology and Toxicology and ^¶Pediatrics, School of Medicine, University of Louisville, Louisville, Kentucky 40202

Islet transplantation is a promising therapy for Type 1 diabetes, but many attempts have failed due to early graft hypoxia or immune rejection, which generate reactive oxygen species (ROS). In the current study, we determined that transgenic overexpression of the antioxidant metallothionein (MT) in pancreatic beta cells provided broad resistance to oxidative stress by scavenging most kinds of ROS including H₂O₂, peroxynitrite radical released from streptozotocin, 3-morpholinosydnonimine (SIN-1), and superoxide radical produced by xanthine/xanthine oxidase. MT also reduced nitric oxide-induced beta cell death. A direct test of hypoxia/reperfusion sensitivity was made by exposing FVB and MT islets to hypoxia (1% O₂). MT markedly reduced ROS production and improved islet cell survival. Because MT protected beta cells from a broad spectrum of ROS and from hypoxia, we considered it to be an ideal candidate for improving islet transplantation. We first tested syngeneic transplantation by implanting islets under the kidney capsule of the same strain, FVB mice, thereby eliminating the immune rejection component. Under these conditions, MT islets maintained much greater insulin content than control islets. Allotransplantation was then tested. MT transgenic and normal FVB islets were implanted under the kidney capsule of BALB/c mice that were previously treated with streptozotocin to induce diabetes. We found that MT islets extended the duration of euglycemia 2-fold longer than nontransgenic islets. The benefit of MT was due to protection from ROS since nitrotyrosine staining, an indicator of free radical damage, was much lower in MT grafts than in FVB grafts. The time course of protection suggested that the major mode of MT action may have been protection from hypoxia or hypoxia/reperfusion. These data demonstrate that treatment with a broad spectrum antioxidant protects islets from ROS damage such as that produced during the early phase of islet transplantation.

Received for publication, July 21, 2003 , and in revised form, October 13, 2003.

^* This work was supported by National Institutes of Health Grants RO1-DK52309 and RO1-DK58100 and P20 RR017702 from the COBRE Program of the National Center for Research Resources. 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.

Both authors equally contributed to this work.

^|| To whom correspondence should be addressed. Tel.: 502-852-2655; Fax: 502-852-2215; E-mail: paul.epstein{at}louisville.edu.

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