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Repetitive Fragmentation Products of Albumin and 1-Antitrypsin in Glomerular Diseases Associated with Nephrotic Syndrome

Giovanni Candiano^*, Luca Musante^*,, Maurizio Bruschi^*,, Andrea Petretto, Laura Santucci^*,, Piero Del Boccio^,||,¶, Barbara Pavone^,||,¶, Francesco Perfumo^**, Andrea Urbani^,||,¶, Francesco Scolari and Gian Marco Ghiggeri^*

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

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; labnefro{at}ospedale-gaslini.ge.it

Received for publication May 17, 2006. Accepted for publication August 7, 2006.

Even if nephrotic syndrome is characterized by massive urinary loss of major plasma proteins, a clear structural characterization based on proteomics has never been reported. Urine and plasma of 23 patients with different idiopathic nephrotic syndromes (10 steroid-sensitive minimal-change nephropathy, seven steroid-resistant FSGS, and six membranous glomerulonephritis) were analyzed with two-dimensional electrophoresis in soft gel, Western blot, and matrix-assisted laser desorption/ionization time of flight mass spectrometry; 72 urinary components corresponded to fragments of albumin and/or of 1-antitrypsin. Several repetitive fragmentation motives and a few differences among different pathologies were found. Several (21 of 72) urinary albumin fragments also were detected in plasma, although in lower concentration, suggesting a preferential excretion. The bulk of components with low molecular weight were detected only in urine, suggesting an in situ formation; zymograms with albumin as substrate showed the presence in urine of specific proteases. A final but not secondary point was the characterization of albumin adducts that harbor both the COOH and NH2 terminal parts of the protein, suggesting the formation of new covalent chemical groups. Altogether, these new findings reveal unexpected structural and functional aspects of proteinuria that may play a key role in pathogenesis. Characterization of urinary fragmentation patterns should be extended to other renal diseases.

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