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Originally published online as doi:10.2353/ajpath.2009.080464 on March 26, 2009

Published online before print March 26, 2009
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(American Journal of Pathology. 2009;174:1827-1836.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080464

SPARC Accelerates Disease Progression in Experimental Crescentic Glomerulonephritis

Amy N. Sussman, Tong Sun, Ronald M. Krofft and Raghu V. Durvasula

From the Department of Medicine, Division of Nephrology, University of Washington School of Medicine, Seattle, Washington

Podocytopenia characterizes many forms of glomerular disease, preceding the development of glomerulosclerosis. While detachment of viable podocytes from the underlying glomerular basement membrane is an important mechanism of podocyte loss, the underlying factors involved remain unclear. Secreted protein acidic and rich in cysteine (SPARC), a matricellular protein with counteradhesive properties, is normally expressed at low levels by the podocyte but is markedly increased following podocyte injury. Accordingly, we elucidate the role of SPARC in mediating experimental crescentic glomerulonephritis by inducing passive nephrotoxic nephritis in SPARC+/+ and SPARC–/– mice. By days 4, 7, and 21 following disease induction, podocyte number is better preserved, glomerulosclerosis is ameliorated, and proteinuria is reduced in SPARC–/– mice as compared with SPARC+/+ littermates. Moreover, the preserved podocyte number in SPARC–/– mice correlates with reduced urinary levels of both nephrin and podocin. To establish a causal role for SPARC in mediating detachment, cultured SPARC+/+ and SPARC–/– podocytes were subjected to mechanical strain as well as trypsin digestion, and detachment assays were performed. While podocytes lacking SPARC were more resistant to stretch-induced detachment, stable re-expression of SPARC restored detachment rates to levels comparable with SPARC+/+ podocytes. Taken together, this study proves that SPARC plays a causal role in mediating podocyte detachment and accelerating glomerulosclerosis in experimental crescentic glomerulonephritis.


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