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Agmatine Inhibits Cell Proliferation and Improves Renal Function in Anti—Thy-1 Glomerulonephritis

Division of Nephrology-Hypertension and Pathology, University of California, Department of Medicine, San Diego, and VA San Diego Healthcare System, La Jolla, California.

Correspondence to Dr. Roland C. Blantz, Professor and Head, Division of Nephrology-Hypertension, UCSD & VA Medical Center, 3350 La Jolla Village Drive, San Diego, CA 92161. Phone: 619-552-7528; Fax: 619-552-7549; E-mail: rblantz{at}ucsd.edu

Abstract. Changes in the expression of alternate arginine metabolic pathways have been implicated in the pathogenesis of experimental glomerulonephritis. Agmatine, decarboxylated arginine, has been shown in vitro to suppress both inducible nitric oxide synthase and the rate-limiting enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC). This study was undertaken to determine whether agmatine administration could reduce tissue injury by decreasing nitric oxide, and reduce cell proliferation, by diminishing ODC activity, in experimental mesangial proliferative glomerulonephritis (Thy-1 nephritis). Agmatine treatment (50 mg/kg per d intraperitoneally) in Thy-1 nephritis rats prevented a reduction in GFR at day 1. Agmatine treatment decreased nitric oxide production in Thy-1 nephritis rats by 23% and 41% at days 1 and 4, respectively. Agmatine treatment also reduced ODC activity and glomerular ³H-thymidine incorporation on days 1, 4, and 7. Histologic evaluation revealed a decline in mesangial cell proliferation and extracellular matrix accumulation associated with agmatine treatment administered before or 24 h after Thy-1 antibody, and this was confirmed by a reduction in the number of cells expressing proliferating cell nuclear antigen on days 4 and 7. These studies provide the first in vivo evidence that agmatine administration can reduce cellular proliferation in Thy-1 nephritis and attenuate the initial reduction in renal function associated with this model.

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