The serum amyloid A3 promoter-driven luciferase reporter mice is a valuable tool to image early renal fibrosis development and shows the therapeutic effect of glucosyl-hesperidin treatment

Sci Rep. 2019 Oct 1;9(1):14101. doi: 10.1038/s41598-019-50685-0.


Tubulointerstitial fibrosis is a progressive process affecting the kidneys, causing renal failure that can be life-threatening. Thus, renal fibrosis has become a serious concern in the ageing population; however, fibrotic development cannot be diagnosed early and assessed noninvasively in both patients and experimental animal models. Here, we found that serum amyloid A3 (Saa3) expression is a potent indicator of early renal fibrosis; we also established in vivo Saa3/C/EBPβ-promoter bioluminescence imaging as a sensitive and specific tool for early detection and visualization of tubulointerstitial fibrosis. Saa3 promoter activity is specifically upregulated in parallel with tumor necrosis factor α (TNF-α) and fibrotic marker collagen I in injured kidneys. C/EBPβ, upregulated in injured kidneys and expressed in tubular epithelial cells, is essential for the increased Saa3 promoter activity in response to TNF-α, suggesting that C/EBPβ plays a crucial role in renal fibrosis development. Our model successfully enabled visualization of the suppressive effects of a citrus flavonoid derivative, glucosyl-hesperidin, on inflammation and fibrosis in kidney disease, indicating that this model could be widely used in exploring therapeutic agents for fibrotic diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • Cell Line
  • Fibrosis / drug therapy*
  • Fibrosis / genetics
  • Flavonoids / pharmacology
  • Glucosides / pharmacology*
  • Hesperidin / analogs & derivatives*
  • Hesperidin / pharmacology
  • Humans
  • Kidney / drug effects
  • Kidney Diseases / drug therapy*
  • Kidney Diseases / genetics
  • Luciferases / genetics*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Promoter Regions, Genetic / drug effects*
  • Promoter Regions, Genetic / genetics
  • Serum Amyloid A Protein / genetics*
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics
  • Tumor Necrosis Factor-alpha / genetics


  • CCAAT-Enhancer-Binding Protein-beta
  • Flavonoids
  • Glucosides
  • Saa3 protein, mouse
  • Serum Amyloid A Protein
  • Tumor Necrosis Factor-alpha
  • glucosyl hesperidin
  • Hesperidin
  • Luciferases