title: C-X-C Chemokine Receptor Type 4 Plays a Crucial Role in Mediating Oxidative Stress-Induced Podocyte Injury.
abstract: Oxidative stress plays a role in mediating podocyte injury and proteinuria. However, the underlying mechanism remains poorly understood. In this study, we investigated the potential role of C-X-C chemokine receptor type 4 (CXCR4), the receptor for stromal cell-derived factor 1α (SDF-1α), in mediating oxidative stress-induced podocyte injury.
  
  
  
  In mouse model of adriamycin nephropathy (ADR), CXCR4 expression was significantly induced in podocytes as early as 3 days. This was accompanied by an increased upregulation of oxidative stress in podocyte, as demonstrated by malondialdehyde assay, nitrotyrosine staining and secretion of 8-hydroxy-2'-deoxyguanosine in urine, and induction of NOX2 and NOX4, major subunits of NADPH oxidase. CXCR4 was also induced in human kidney biopsies with proteinuric kidney diseases and colocalized with advanced oxidation protein products (AOPPs), an established oxidative stress trigger. Using cultured podocytes and mouse model, we found that AOPPs induced significant loss of podocyte marker Wilms tumor 1 (WT1), nephrin, and podocalyxin, accompanied by upregulation of desmin both in vitro and in vivo. Furthermore, AOPPs worsened proteinuria and aggravated glomerulosclerosis in ADR. These effects were associated with marked activation of SDF-1α/CXCR4 axis in podocytes. Administration of AMD3100, a specific inhibitor of CXCR4, reduced proteinuria and ameliorated podocyte dysfunction and renal fibrosis triggered by AOPPs in mice. In glomerular miniorgan culture, AOPPs also induced CXCR4 expression and downregulated nephrin and WT1. Innovation and Conclusion: These results suggest that chemokine receptor CXCR4 plays a crucial role in mediating oxidative stress-induced podocyte injury, proteinuria, and renal fibrosis. CXCR4 could be a new target for mitigating podocyte injury, proteinuria, and glomerular sclerosis in proteinuric chronic kidney disease. Antioxid. Redox Signal. 27, 345-362.
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors.forename: Hongyan
authors.initials: H
authors.lastname: Mo
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors.forename: Qinyu
authors.initials: Q
authors.lastname: Wu
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors.forename: Jinhua
authors.initials: J
authors.lastname: Miao
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors.forename: Congwei
authors.initials: C
authors.lastname: Luo
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors.forename: Xue
authors.initials: X
authors.lastname: Hong
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors.forename: Yongping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 2 Guangdong Provincial Key Laboratory of New Drug Screening, Department of Biopharmaceutics, School of Pharmaceutical Sciences, Southern Medical University , Guangzhou, China .
authors.forename: Lan
authors.initials: L
authors.lastname: Tang
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .|3 Department of Pathology, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Youhua
authors.initials: Y
authors.lastname: Liu
authors.affiliation: 1 State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University , Guangzhou, China .
authors.forename: Lili
authors.initials: L
authors.lastname: Zhou
mesh_terms: D062107:Advanced Oxidation Protein Products / Q000378:metabolism; D000818:Animals; D001596:Benzylamines; D001706:Biopsy; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology*; D000080027:Cyclams; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D051379:Mice; D018384:Oxidative Stress; D050199:Podocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D011507:Proteinuria / Q000378:metabolism / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000378:metabolism*
chemical_list: D062107:Advanced Oxidation Protein Products; D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D004317:Doxorubicin; C088327:plerixafor
keywords: CXCR4; oxidative stress; podocyte injury