Abstract
The functional contribution of myofibroblasts in fibrosis is not well understood1,2,3. Using a new genetic mouse model to track and isolate myofibroblasts, we performed gene expression profiling followed by biological validation to identify HE4 (encoding human epididymis protein 4, also known as WAP 4-disulfide core domain-2 or Wfdc2) as the most upregulated gene in fibrosis-associated myofibroblasts. The HE4 gene encodes for a putative serine protease inhibitor that is upregulated in human and mouse fibrotic kidneys and is elevated in the serum of patients with kidney fibrosis. HE4 suppresses the activity of multiple proteases, including serine proteases and matrix metalloproteinases, and specifically inhibits their capacity to degrade type I collagen. In particular, we identified two serine proteases, Prss35 and Prss23, as HE4 targets with functional relevance in kidney fibrosis. Administration of HE4-neutralizing antibodies accelerated collagen I degradation and inhibited fibrosis in three different mouse models of renal disease. Collectively these studies suggest that HE4 is a potential biomarker of renal fibrosis and a new therapeutic target.
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Acknowledgements
This study was supported by US National Institutes of Health (NIH) grants DK55001, DK081976, CA125550, CA155370, CA151925 and CA163191, funding from the Harvard Stem Cell Institute, the Metastasis Research Center at the MD Anderson Cancer Center and the Cancer Prevention and Research Institute of Texas (all to R.K.). V.S.L. was funded from the NIH Research Training grant in Gastroenterology (2T32DK007760-11), H.S. was funded by the NIH Research Training grant in Cardiovascular Biology (5T32HL007374-30), and J.T.O. was funded by the NIH Cell and Development Biology Training grant GM07226 and the Department of Defense Breast Cancer Predoctoral Traineeship Award BC083229.
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R.K. provided intellectual input and the conceptual framework, designed the study and helped in the writing of the manuscript. V.S.L. designed the study, provided intellectual input, performed experiments, collected data and wrote the manuscript. Y.T., J.T.O. and H.S. performed some experiments and collected data. D.C., G.A.M. and C.A.M. provided human samples for analysis.
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LeBleu, V., Teng, Y., O'Connell, J. et al. Identification of human epididymis protein-4 as a fibroblast-derived mediator of fibrosis. Nat Med 19, 227–231 (2013). https://doi.org/10.1038/nm.2989
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DOI: https://doi.org/10.1038/nm.2989
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