RAGE mediates podocyte injury in adriamycin-induced glomerulosclerosis.
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.
Guo
Jiancheng
J
Department of Surgery, Columbia University Medical Center, New York, New York 10025, USA.
Ananthakrishnan
Radha
R
Qu
Wu
W
Lu
Yan
Y
Reiniger
Nina
N
Zeng
Shan
S
Ma
Wanchao
W
Rosario
Rosa
R
Yan
Shi Fang
SF
Ramasamy
Ravichandran
R
D'Agati
Vivette
V
Schmidt
Ann Marie
AM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D004317:Doxorubicin / Q000633:toxicity; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D050199:Podocytes / Q000378:metabolism* / Q000473:pathology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
D000903:Antibiotics, Antineoplastic; D017127:Glycation End Products, Advanced; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D004317:Doxorubicin; D019255:NADPH Oxidases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3