Peroxidasin Is Secreted and Incorporated into the Extracellular Matrix of Myofibroblasts and Fibrotic Kidney

Zalán Péterfi^*, Ágnes Donkó^*, Anna Orient^*, Adrienn Sum^*, Ágnes Prókai, Beáta Molnár^*, Zoltán Veréb, Éva Rajnavölgyi, Krisztina J. Kovács, Veronika Müller^¶, Attila J. Szabó and Miklós Geiszt^*

From the Department of Physiology,^* the First Department of Pediatrics, and the Department of Pulmonology,^¶ Semmelweis University, Faculty of Medicine, Budapest; the Institute of Immunology, University of Debrecen, Medical and Health Science Center, Debrecen; and the Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Budapest, Hungary

Mammalian peroxidases are heme-containing enzymes that servediverse biological roles, such as host defense and hormone biosynthesis.A mammalian homolog of Drosophila peroxidasin belongs to theperoxidase family; however, its function is currently unknown.In this study, we show that peroxidasin is present in the endoplasmicreticulum of human primary pulmonary and dermal fibroblasts,and the expression of this protein is increased during transforminggrowth factor-β1-induced myofibroblast differentiation.Myofibroblasts secrete peroxidasin into the extracellular spacewhere it becomes organized into a fibril-like network and colocalizeswith fibronectin, thus helping to form the extracellular matrix.We also demonstrate that peroxidasin expression is increasedin a murine model of kidney fibrosis and that peroxidasin localizesto the peritubular space in fibrotic kidneys. In addition, weshow that this novel pathway of extracellular matrix formationis unlikely mediated by the peroxidase activity of the protein.Our data indicate that peroxidasin secretion represents a previouslyunknown pathway in extracellular matrix formation with a potentiallyimportant role in the physiological and pathological fibrogenicresponse.