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Fibroblasts in Kidney Fibrosis Emerge via Endothelial-to-Mesenchymal Transition

Elisabeth M. Zeisberg^*, Scott E. Potenta^*, Hikaru Sugimoto^*, Michael Zeisberg^* and Raghu Kalluri^*,,

^* Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Department of Biological Chemistry and Molecular Pharmacology, and Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts

Correspondence: Dr. Raghu Kalluri, Department of Medicine, Harvard Medical School, Division of Matrix Biology, Department of Medicine, CLS 11086, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, 3 Blackfan Circle, Boston, MA 02215. Phone: 617-735-4601; Fax: 617-735-4602; E-mail: rkalluri{at}bidmc.harvard.edu

Received for publication May 19, 2008. Accepted for publication August 18, 2008.

Fibroblasts are key mediators of fibrosis in the kidney and other organs, but their origin during fibrosis is still not completely clear. Activated fibroblasts likely arise from resident quiescent fibroblasts via epithelial-to-mesenchymal transition and from the bone marrow. Here, we demonstrate that endothelial cells also contribute to the emergence of fibroblasts during kidney fibrosis via the process of endothelial-to-mesenchymal transition (EndMT). We examined the contribution of EndMT to renal fibrosis in three mouse models of chronic kidney disease: (1) Unilateral ureteral obstructive nephropathy, (2) streptozotocin-induced diabetic nephropathy, and (3) a model of Alport renal disease. Approximately 30 to 50% of fibroblasts coexpressed the endothelial marker CD31 and markers of fibroblasts and myofibroblasts such as fibroblast specific protein-1 and -smooth muscle actin. Endothelial lineage tracing using Tie2-Cre;R26R-stop-EYFP transgenic mice further confirmed the presence of EndMT-derived fibroblasts. Collectively, our results demonstrate that EndMT contributes to the accumulation of activated fibroblasts and myofibroblasts in kidney fibrosis and suggest that targeting EndMT might have therapeutic potential.

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