Advanced glycation end-product-induced mitogenesis is dependent on Janus kinase 2-induced heat shock protein 70 in normal rat kidney interstitial fibroblast cells

Transl Res. 2007 May;149(5):274-81. doi: 10.1016/j.trsl.2006.08.005.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cyclin D1 / metabolism
  • Cyclin E / metabolism
  • Fibroblasts / cytology*
  • Glycation End Products, Advanced / pharmacology
  • Glycation End Products, Advanced / physiology*
  • HSP72 Heat-Shock Proteins / metabolism
  • HSP72 Heat-Shock Proteins / physiology*
  • Janus Kinase 2 / physiology*
  • Kidney / cytology*
  • Mitosis / drug effects
  • Mitosis / physiology*
  • Phosphorylation / drug effects
  • Protein Interaction Mapping
  • Rats
  • Reactive Oxygen Species / metabolism
  • STAT1 Transcription Factor / metabolism
  • STAT3 Transcription Factor / metabolism
  • STAT5 Transcription Factor / metabolism
  • Transcription Factors / metabolism
  • Tyrosine / metabolism


  • Cyclin E
  • Glycation End Products, Advanced
  • HSP72 Heat-Shock Proteins
  • Reactive Oxygen Species
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat1 protein, rat
  • Stat3 protein, rat
  • Stat5b protein, rat
  • Transcription Factors
  • Cyclin D1
  • Tyrosine
  • Janus Kinase 2