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Active Focal Segmental Glomerulosclerosis Is Associated with Massive Oxidation of Plasma Albumin

Luca Musante^*,, Giovanni Candiano^*, Andrea Petretto, Maurizio Bruschi^*,, Nazzareno Dimasi, Gianluca Caridi^*, Barbara Pavone^||,¶,**, Piero Del Boccio^||,¶,**, Monica Galliano, Andrea Urbani^||,¶,**, Francesco Scolari, Flavio Vincenti and Gian Marco Ghiggeri^*

^* Laboratory on Pathophysiology of Uremia, Mass Spectrometry Core Facility, Laboratory of Molecular Medicine, G. Gaslini Children Hospital, and Renal Child Foundation, Genoa, ^|| Department of Biomedical Science, Università degli Studi di Chieti e Pescara, Chieti, ^¶ Centro Studi sull’Invecchiamento, Fondazione Università "G. D’Annunzio," Chieti, ^** IRCCS-Fondazione Santa Lucia, Rome, Department of Biochemistry, University of Pavia, Pavia, and Department of Nephrology, University of Brescia, Brescia, Italy; and Transplant Service, University of California, San Francisco, San Francisco, California

Address correspondence to: Dr. Gian Marco Ghiggeri, Laboratory on Pathophysiology of Uremia, G. Gaslini Children Hospital, Largo G. Gaslini, 5. 16148 Genova, Italy. Phone: +39-010-380742; Fax: +39-010-395214; E-mail: labnefro{at}ospedale-gaslini.ge.it

Received for publication September 6, 2006. Accepted for publication December 18, 2006.

The basic mechanism for idiopathic FSGS still is obscure. Indirect evidence in humans and generation of FSGS by oxidants in experimental models suggest a role of free radicals. In vitro studies demonstrate a main role of plasma albumin as antioxidant, its modification representing a chemical marker of oxidative stress. With the use of complementary liquid chromatography electron spray ionization tandem mass spectrometry (LC-ESI-MS/MS) and biochemical methods, plasma albumin was characterized in 34 patients with FSGS; 18 had received a renal transplant, and 17 had IgM mesangial deposition. Patients with FSGS that was in remission or without recurrence after transplantation had normal plasma albumin, and the same occurred in patients with primary and secondary nephrites and with chronic renal failure. In contrast, patients with active FSGS or with posttransplantation recurrence had oxidized plasma albumin. This finding was based on the characterization of albumin Cys 34 with an mass-to-charge ratio of 511.71 in triple charge that was consistent with the formation of a cysteic acid carrying a sulfonic group (alb-SO₃^–). The exact mass of albumin was increased accordingly (+48 Da) for incorporation of three oxygen radicals. Direct titration of the free sulfhydryl group 34 of plasma albumin and electrophoretic titration curves confirmed loss of free sulfhydryl group and formation of a fast-moving isoform in all cases with disease activity. This is the first demonstration of in vivo plasma albumin oxidation that was obtained with an adequate structural approach. Albumin oxidation seems to be specific for FSGS, suggesting some pathogenetic implications. Free radical involvement in FSGS may lead to specific therapeutic interventions.

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J. Am. Soc. Nephrol. 2007 18: 661-662. [Full Text] [PDF]

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