title: Nuclear receptor NR5A2 is involved in the calreticulin gene regulation during renal fibrosis.
abstract: Renal fibrosis is a common histological finding present in many pathologies; however, key signaling pathways and molecular determinants involved in the development of fibrosis are not fully known yet. Previous findings have established a causative role of calreticulin's up-regulation during the development of renal fibrosis while its down-regulation exhibited a protective effect against fibrosis. Therefore, the mechanism of its up-regulation needs to be explored.
  
  
  
  Bioinformatics analyses of the calreticulin gene promoter combined with transcriptional assays and in vivo chromatin immunoprecipitation experiments in the Unilateral Ureteric Obstruction (UUO) model of renal fibrosis, indicated that NR5A2 is a critical regulator of calreticulin expression. To confirm this finding, and further study post-translational modifications of NR5A2, real time RT-qPCR, immunohistochemistry and Western blotting experiments were performed.
  
  
  
  NR5A2 is up-regulated at both mRNA and protein level during kidney fibrosis in the UUO model. The post-translational modification of SUMOylation was identified as a critical parameter in this phenomenon and SUMOylation was observed to be up-regulated during the development of renal fibrosis. The enzyme Ubc9, critical for the process of SUMOylation was also upregulated at mRNA and protein level during the process.
  
  
  
  These data establish for the first time a role for NR5A2 and its SUMOylation on the transcriptional regulation of the calreticulin gene in a rodent model of renal fibrosis and raise the possibility that NR5A2 might be a novel target for future anti-fibrotic interventions.
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Arvaniti
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Athina
authors.initials: A
authors.lastname: Vakrakou
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Valeria
authors.initials: V
authors.lastname: Kaltezioti
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Stergiopoulos
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Greece.
authors.forename: Niki
authors.initials: N
authors.lastname: Prakoura
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Greece. Electronic address: ppolitis@bioacademy.gr.
authors.forename: Panagiotis K
authors.initials: PK
authors.lastname: Politis
authors.affiliation: Biomedical Research Foundation of the Academy of Athens, Greece. Electronic address: acharonis@bioacademy.gr.
authors.forename: Aristidis
authors.initials: A
authors.lastname: Charonis
mesh_terms: D000818:Animals; D037282:Calreticulin / Q000235:genetics*; D002460:Cell Line; D004195:Disease Models, Animal; D005355:Fibrosis; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D007668:Kidney / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism; D058207:Sumoylation; D044763:Ubiquitin-Conjugating Enzymes / Q000037:antagonists & inhibitors; D015854:Up-Regulation; D014517:Ureteral Obstruction / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D037282:Calreticulin; C082631:NR5A2 protein, human; C431936:Nr5a2 protein, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D025842:SUMO-1 Protein; D044763:Ubiquitin-Conjugating Enzymes; D000098843:Ubiquitin-Conjugating Enzyme UBC9
keywords: Fibrosis; Obstructive nephropathy; Proximal tubule; Transcription regulation