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J. Biol. Chem., Vol. 280, Issue 33, 29946-29955, August 19, 2005

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Accelerated Glucose Intolerance, Nephropathy, and Atherosclerosis in Prostaglandin D₂ Synthase Knock-out Mice^*

Louis Ragolia¶, Thomas Palaia, Christopher E. Hall, John K. Maesaka, Naomi Eguchi||**, and Yoshihiro Urade||

From the Vascular Biology Laboratory, Winthrop-University Hospital, Mineola, New York 11501, Stony Brook University School of Medicine, Stony Brook, New York 11794, and the ^||Osaka Bioscience Institute, Osaka, Japan

Type 2 diabetics have an increased risk of developing atherosclerosis, suggesting the mechanisms that cause this disease are enhanced by insulin resistance. In this study we examined the effects of gene knock-out (KO) of lipocalin-type prostaglandin D₂ synthase (L-PGDS), a protein found at elevated levels in type 2 diabetics, on diet-induced glucose tolerance and atherosclerosis. Our results show that L-PGDS KO mice become glucose-in-tolerant and insulin-resistant at an accelerated rate when compared with the C57BL/6 control strain. Adipocytes were significantly larger in the L-PGDS KO mice compared with controls on the same diets. Cell culture data revealed significant differences between insulin-stimulated mitogen-activated protein kinase phosphatase-2, protein-tyrosine phosphatase-1D, and phosphorylated focal adhesion kinase expression levels in L-PGDS KO vascular smooth muscle cells and controls. In addition, only the L-PGDS KO mice developed nephropathy and an aortic thickening reminiscent to the early stages of atherosclerosis when fed a "diabetogenic" high fat diet. We conclude that L-PGDS plays an important role regulating insulin sensitivity and atherosclerosis in type 2 diabetes and may represent a novel model of insulin resistance, atherosclerosis, and diabetic nephropathy.

Received for publication, March 16, 2005 , and in revised form, June 21, 2005.

^* This work was supported by an American Diabetes Association Career Development Award, National Institute of Health Grant R01HL06 7953-01A2, and the Winthrop-University Hospital Department of Medicine. 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.

^** Present address: Waseda-Olympus Bioscience Research Institute, Helios, 05-01/02, 11 Biopolis Way, Singapore 138667.

^¶ To whom correspondence should be addressed: Vascular Biology Institute, Winthrop-University Hospital, 222 Station Plaza North, Suite 505-B, Mineola, NY 11501. Tel.: 516-663-2028; Fax: 516-663-4710; E-mail: lragolia{at}winthrop.org.

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