Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells

J Cell Biochem. 2001;81(1):102-13. doi: 10.1002/1097-4644(20010401)81:1<102::aid-jcb1027>;2-y.


Advanced glycation end-product (AGE) is important in the pathogenesis of diabetic nephropathy (DN), and captopril (an angiotensin converting enzyme inhibitor) is effective in treating this disorder. We have shown that the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) cascade is responsible for AGE-induced mitogenesis in NRK-49F (normal rat kidney fibroblast) cells, but its role in renal fibrosis in DN remains unknown. Therefore, we have sought to determine whether JAK/STAT is involved in AGE-regulated collagen production in NRK-49F cells. We found that AGE time (1-7 days) and dose (10-200 microg/ml)-dependently increased collagen production in these cells. Additionally, AGE increased RAGE (receptor for AGE) protein expression. AGE-induced RAGE expression was dose-dependently inhibited by antisense RAGE oligodeoxynucleotide (ODN) and captopril. AGE-induced type I collagen production and JAK2-STAT1/STAT3 activation were decreased by AG-490 (a specific JAK2 inhibitor), antisense RAGE ODN and captopril. Meanwhile, STAT1 and STAT3 decoy ODNs also suppressed the induction of collagen by AGE. We concluded that RAGE and the JAK2-STAT1/STAT3 pathway were involved in AGE-induced collagen production in NRK-49F cells. Furthermore, captopril was found to reverse AGE-induced collagen production, probably by attenuating RAGE expression and JAK2-STAT1/STAT3 activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Captopril / pharmacology
  • Cell Line
  • Collagen / biosynthesis*
  • DNA Primers
  • DNA-Binding Proteins / metabolism*
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Glycation End Products, Advanced*
  • Janus Kinase 2
  • Kinetics
  • Oligonucleotides, Antisense / pharmacology
  • Phosphorylation
  • Protein-Tyrosine Kinases / metabolism*
  • Proto-Oncogene Proteins*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction*
  • Trans-Activators / metabolism*
  • Tyrosine / metabolism
  • Tyrphostins / pharmacology


  • DNA Primers
  • DNA-Binding Proteins
  • Glycation End Products, Advanced
  • Oligonucleotides, Antisense
  • Proto-Oncogene Proteins
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Trans-Activators
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Tyrosine
  • Collagen
  • Captopril
  • Protein-Tyrosine Kinases
  • Jak2 protein, rat
  • Janus Kinase 2