title: GADD45B mediates podocyte injury in zebrafish by activating the ROS-GADD45B-p38 pathway.
abstract: GADD45 gene has been implicated in cell cycle arrest, cell survival or apoptosis in a cell type specific and context-dependent manner. Members of GADD45 gene family have been found differentially expressed in several podocyte injury models, but their roles in podocytes are unclear. Using an in vivo zebrafish model of inducible podocyte injury that we have previously established, we found that zebrafish orthologs of gadd45b were induced upon the induction of podocyte injury. Podocyte-specific overexpression of zebrafish gadd45b exacerbated edema, proteinuria and foot-process effacement, whereas knockdown of gadd45b by morpholino-oligos in zebrafish larvae ameliorated podocyte injury. We then explored the role of GADD45B induction in podocyte injury using in vitro podocyte culture. We confirmed that GADD45B was significantly upregulated during the early phase of podocyte injury in cultured human podocytes and that podocyte apoptosis induced by TGF-β and puromycin aminonucleoside (PAN) was aggravated by GADD45B overexpression but ameliorated by shRNA-mediated GADD45B knockdown. We also showed that ROS inhibitor NAC suppressed PAN-induced GADD45B expression and subsequent activation of p38 MAPK pathway in podocytes and that inhibition of GADD45B diminished PAN-induced p38 MAPK activation. Taken together, our findings demonstrated that GADD45B has an important role in podocyte injury and may be a therapeutic target for the management of podocyte injury in glomerular diseases.
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.|Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wan
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Hou
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: S
authors.initials: S
authors.lastname: Shi
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhu
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: C
authors.initials: C
authors.lastname: Zeng
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.|Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: W
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.affiliation: National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism*; D017209:Apoptosis; D050199:Podocytes / Q000378:metabolism*; D017382:Reactive Oxygen Species; D014162:Transfection; D015027:Zebrafish / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D017382:Reactive Oxygen Species; D029961:Zebrafish Proteins; C000597099:gadd45ba protein, zebrafish; D000097642:GADD45 Proteins