Peroxidasin and eosinophil peroxidase, but not myeloperoxidase, contribute to renal fibrosis in the murine unilateral ureteral obstruction model

• Published in: American journal of physiology. Renal physiology 2019-02, Vol.316 (2), p.F360-F371
• Main Authors: Colon, Selene, Luan, Haiyan, Liu, Yan, Meyer, Cameron, Gewin, Leslie, Bhave, Gautam
• Format: Article
• Language: English
• Subjects: Acids; Animals; Cell Movement; Disease Models, Animal; Eosinophil Peroxidase - deficiency; Eosinophil Peroxidase - genetics; Eosinophil Peroxidase - metabolism; Eosinophils - enzymology; Eosinophils - pathology; Extracellular Matrix Proteins - deficiency; Extracellular Matrix Proteins - genetics; Extracellular Matrix Proteins - metabolism; Female; Fibrosis; Heme; Hydrogen peroxide; Hypochlorous acid; Kidney - enzymology; Kidney - pathology; Kidney diseases; Leukocytes (eosinophilic); Male; Mice, Inbred C57BL; Mice, Knockout; Nephritis, Interstitial - enzymology; Nephritis, Interstitial - etiology; Nephritis, Interstitial - pathology; Nephritis, Interstitial - prevention & control; Oxidation; Peroxidase; Peroxidase - deficiency; Peroxidase - genetics; Peroxidase - metabolism; Peroxidases - deficiency; Peroxidases - genetics; Peroxidases - metabolism; Peroxidasin; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Signal Transduction; Superoxide; Therapeutic applications; Ureteral Obstruction - complications; Ureteral Obstruction - enzymology; Ureteral Obstruction - pathology
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00291.2018

Renal fibrosis is the pathological hallmark of chronic kidney disease (CKD) and manifests as glomerulosclerosis and tubulointerstitial fibrosis. Reactive oxygen species contribute significantly to renal inflammation and fibrosis, but most research has focused on superoxide and hydrogen peroxide (H O ). The animal heme peroxidases myeloperoxidase (MPO), eosinophil peroxidase (EPX), and peroxidasin (PXDN) uniquely metabolize H O into highly reactive and destructive hypohalous acids, such as hypobromous and hypochlorous acid. However, the role of these peroxidases and their downstream hypohalous acids in the pathogenesis of renal fibrosis is unclear. Our study defines the contribution of MPO, EPX, and PXDN to renal inflammation and tubulointerstitial fibrosis in the murine unilateral ureteral obstruction (UUO) model. Using a nonspecific inhibitor of animal heme peroxidases and peroxidase-specific knockout mice, we find that loss of EPX or PXDN, but not MPO, reduces renal fibrosis. Furthermore, we demonstrate that eosinophils, the source of EPX, accumulate in the renal interstitium after UUO. These findings point to EPX and PXDN as potential therapeutic targets for renal fibrosis and CKD and suggest that eosinophils modulate the response to renal injury.