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J. Biol. Chem., Vol. 283, Issue 11, 6744-6751, March 14, 2008

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2 but Not 1 AMP-activated Protein Kinase Mediates Oxidative Stress-induced Inhibition of Retinal Pigment Epithelium Cell Phagocytosis of Photoreceptor Outer Segments^*

From the Retinal Disease Research, Department of Biological Sciences, Allergan, Incorporated, Irvine, California 92612

Oxidative stress causes retinal pigment epithelium (RPE) cell dysfunction and is a major risk factor leading to the development of dry-type age-related macular degeneration. Taking pharmacological and genetic approaches, we address the mechanisms by which sublethal oxidative stress inhibits RPE cell phagocytosis. Sublethal oxidative stress dose-dependently inhibited RPE cell phagocytosis of photoreceptor outer segments (POS) and activated AMP-activated protein kinase (AMPK) as determined by increased Thr¹⁷² and Ser⁷⁹ phosphorylation of AMPK and its substrate acetyl-CoA carboxylase, respectively. Similar to oxidative stress, 5-aminoimidazole-4-carboxamide riboside (AICAR), a pharmacological activator of AMPK, inhibited RPE cell phagocytosis of POS in a dose-dependent manner. Inhibition of RPE cell phagocytosis by AICAR was fully reversed by blockade of AICAR translocation into cells by dipyridamole or inhibition of AICAR conversion to ZMP by adenosine kinase inhibitor 5-iodotubercidin. In agreement, AICAR-induced activation of AMPK was abolished by preincubation with dipyridamole or 5-iodotubercidin. Knock-out experiments further revealed that 2 but not 1 AMPK was involved in RPE cell phagocytosis and that activation of 2 AMPK contributed to the inhibition of RPE cell phagocytosis by oxidative stress. Inhibition of RPE cell phagocytosis by activation of 2 AMPK was associated with a dramatic increase in acetyl-CoA carboxylase phosphorylation. In comparison, AMPK had no role in oxidative stress-induced breakdown of RPE barrier function. Taken together, reduction in POS load under oxidative stress might direct RPE cells to a self-protected status. Thus, activating AMPK could have therapeutic potential in treating dry macular degeneration.

Received for publication, October 26, 2007 , and in revised form, January 8, 2008.

^* 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 To whom correspondence should be addressed: RD3-2D, Dept. of Biological Sciences, Allergan, Inc., 2525 Dupont Dr., Irvine, California 92612-1599. Fax: 714-246-2206; E-mail: qin_suofu{at}allergan.com.

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