Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 19, Issue 12, Pages 2282-2287Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2008050513
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Funding
- American Heart Association [DK62987, DK61688, DK55001, AA13913, CA12550, 07356027]
- Mentored Clinical Scientist Development [1K08 CA129204, K08 DK074558]
- National Institutes of Health [GM07226]
- Beth Israel Deaconess Medical Center
- NATIONAL CANCER INSTITUTE [R01CA012550, K08CA129204] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K08DK074558, R01DK061688, R01DK055001, R01DK062987] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007226] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [R01AA013913] Funding Source: NIH RePORTER
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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 alpha-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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