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Proteomic Patterns and Prediction of Glomerulosclerosis and Its Mechanisms

Baogang J. Xu^*, Yu Shyr, Xiubin Liang, Li-jun Ma, Ellen M. Donnert, Jeremy D. Roberts, Xueqiong Zhang, Valentina Kon, Nancy J. Brown^||, Richard M. Caprioli^¶ and Agnes B. Fogo^,,||

^* Cancer Biology, Biostatistics, Pathology, Pediatrics, ^|| Medicine, and ^¶ Biochemistry, Vanderbilt University Medical Center, Nashville, Tennessee

Address correspondence to: Dr. Agnes B. Fogo, MCN C3310, Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232. Phone: 615-322-3114; Fax: 615-343-7023; E-mail: agnes.fogo{at}vanderbilt.edu

Received for publication March 9, 2005. Accepted for publication June 23, 2005.

Protein expression profiles linked to sclerosis in the 5/6 nephrectomy (Nx) rat model of focal segmental glomerulosclerosis were investigated. Sections of control glomeruli from normal baseline Nx tissue and nonsclerotic and sclerotic glomeruli from 12 wk after 5/6 Nx were isolated by laser capture microdissection. Protein profiles were acquired directly by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Classification accuracy was 99.2% for distinguishing normal versus sclerotic glomeruli and 96.7 and 97.8% for nonsclerotic versus normal and sclerotic glomeruli, respectively. The proteomic pattern of the nonsclerotic glomeruli was more similar to sclerotic than normal glomeruli (P < 0.0001). Thymosin 4, a protein with relevant interactions with plasminogen activator inhibitor-1, angiogenesis, and wound healing, was identified as a key differentially expressed protein. Thymosin 4 immunostaining was increased in sclerotic glomeruli, predominantly in endothelial cells. Downregulation of thymosin 4 by RNAi in cultured glomerular endothelial cells decreased angiotensin II–induced plasminogen activator inhibitor-1 expression. In conclusion, proteomic patterns can accurately distinguish normal versus nonsclerotic versus sclerotic glomeruli. The closely related proteomic patterns of nonsclerotic and sclerotic glomeruli suggest early activation of prosclerotic mechanisms even in seemingly intact glomeruli. Thymosin 4 is a marker of such early events and may even contribute to sclerosis.

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