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RAGE Mediates Podocyte Injury in Adriamycin-induced Glomerulosclerosis

Jiancheng Guo^*, Radha Ananthakrishnan^*, Wu Qu^*, Yan Lu^*, Nina Reiniger^*, Shan Zeng^*, Wanchao Ma, Rosa Rosario^*, Shi Fang Yan^*, Ravichandran Ramasamy^*, Vivette D'Agati and Ann Marie Schmidt^*

Departments of ^* Surgery, Ophthalmology, and Pathology, Columbia University Medical Center, New York, New York

Correspondence: Ann Marie Schmidt, Columbia University Medical Center, Department of Surgery, 630 West 168th Street, P&S 17-501, New York, NY 10025. Phone: 212-305-6406; Fax: 212-305-5337; E-mail: ams11{at}columbia.edu

Received for publication October 16, 2007. Accepted for publication December 18, 2007.

In the kidney, the receptor for advanced glycation end products (RAGE) is principally expressed in the podocyte at low levels, but is upregulated in both human and mouse glomerular diseases. Because podocyte injury is central to proteinuric states, such as the nephrotic syndrome, the murine adriamycin nephrosis model was used to explore the role of RAGE in podocyte damage. In this model, administration of the anthracycline antibiotic adriamycin provokes severe podocyte stress and glomerulosclerosis. In contrast to wild-type animals, adriamycin-treated RAGE-null mice were significantly protected from effacement of the podocyte foot processes, albuminuria, and glomerulosclerosis. Administration of adriamycin induced rapid generation of RAGE ligands, and treatment with soluble RAGE protected against podocyte injury and glomerulosclerosis. In vitro, incubation of RAGE-expressing murine podocytes with adriamycin stimulated AGE formation, and treatment with RAGE ligands rapidly activated nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase, via p44/p42 MAP kinase signaling, and upregulated pro-fibrotic growth factors. These data suggest that RAGE may contribute to the pathogenesis of podocyte injury in sclerosing glomerulopathies such as focal segmental glomerulosclerosis.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673