title: Advanced glycation end-product-induced mitogenesis is dependent on Janus kinase 2-induced heat shock protein 70 in normal rat kidney interstitial fibroblast cells.
abstract: Kidney interstitial fibroblast proliferation is important in the pathogenesis of diabetic renal fibrosis. In this regard, advanced glycation end-product (AGE)-induced proliferation in normal rat kidney interstitial fibroblast (NRK-49F) cells is dependent on the Janus kinase 2 (JAK2) signal transducers and activators of transcription (STAT) pathway. Heat shock protein (Hsp) is a molecular target of JAK/STAT. Thus, the role of Hsp70 in AGE-induced mitogenesis in NRK-49F cells was studied. The AGE dose (100-200 microg/mL) and time (16-72 h) dependently increased Hsp70 protein expression. AGE-induced Hsp70 was attenuated by AG-490 (a JAK2 inhibitor) and N-acetylcysteine. AGE also increased tyrosine phosphorylation of Hsp70, cyclin E, and cyclin D1 (to a lesser extent) while increasing Hsp70 protein interactions with STAT1, STAT3, STAT5b, cyclin D1, and cyclin E. AGE-induced tyrosine phosphorylation of Hsp70 and cyclin E (but not cyclin D1) was attenuated by AG-490. AGE-induced mitogenesis, cyclin D1, and cyclin E were attenuated by Hsp70 antisense oligodeoxynucleotide and 2-aminopurine (an Hsp70 inhibitor). AGE-induced Hsp70 and mitogenesis were also attenuated by N-acetylcysteine. It was concluded that AGE-induced Hsp70 protein expression and tyrosine phosphorylation are dependent on JAK2 in NRK-49F cells. AGE increased protein-protein interactions among Hsp70, STAT1, STAT3, STAT5b, cyclin D1, and cyclin E. Moreover, AGE-induced mitogenesis is dependent on Hsp70 and oxidative stress.
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: San-Cher
authors.initials: SC
authors.lastname: Chen
authors.forename: Jinn-Yuh
authors.initials: JY
authors.lastname: Guh
authors.forename: Hung-Chun
authors.initials: HC
authors.lastname: Chen
authors.forename: Yu-Lin
authors.initials: YL
authors.lastname: Yang
authors.forename: Jau-Shyang
authors.initials: JS
authors.lastname: Huang
authors.forename: Lea-Yea
authors.initials: LY
authors.lastname: Chuang
mesh_terms: D000818:Animals; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology*; D017127:Glycation End Products, Advanced / Q000494:pharmacology / Q000502:physiology*; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D053614:Janus Kinase 2 / Q000502:physiology*; D007668:Kidney / Q000166:cytology*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D025941:Protein Interaction Mapping; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D019927:Cyclin E; D017127:Glycation End Products, Advanced; D050884:HSP72 Heat-Shock Proteins; D017382:Reactive Oxygen Species; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; C494097:Stat5b protein, rat; D014157:Transcription Factors; D019938:Cyclin D1; D014443:Tyrosine; D053614:Janus Kinase 2