Dexamethasone induces connective tissue growth factor expression in renal tubular epithelial cells in a mouse strain-specific manner

Am J Pathol. 2006 Mar;168(3):737-47. doi: 10.2353/ajpath.2006.050656.

Abstract

Connective tissue growth factor (CTGF), a downstream mediator of transforming growth factor-beta1, mediates mesangial cell/fibroblast proliferation and extracellular matrix production by renal cells. Here, we show that renal tubular epithelial cells from patients with minimal change nephritic syndrome produced CTGF after glucocorticoid treatment. In addition, the glucocorticoid dexamethasone (DEX) increased CTGF mRNA levels in the kidneys of C57B6 but not SJL mice and produced intermediate CTGF mRNA levels in the kidneys of F1 (C57B6 x SJL) mice, midway between the levels found for parental strains. DEX also increased CTGF mRNA levels in cultured tubular epithelial cells derived from C57B6 (mProx24) but not SJL (MCT) mice via transcriptional up-regulation of CTGF mRNA. Transient transfection experiments using luciferase reporter constructs bearing CTGF promoter fragments revealed that the -897- to -628-bp fragment contained DEX-responsive positive regulatory elements, which were active in mProx24 but not MCT cells. Long-term DEX treatment resulted in fibronectin deposition in the kidneys of C57B6 but not SJL mice, and this effect was inhibited by co-administration of CTGF anti-sense oligodeoxynucleotides. Thus, glucocorticoid-induced renal fibrogenesis seems to be influenced by genetic background, with the critical DEX-responsive elements in the -897- to -628-bp region of the CTGF promoter.

Publication types

  • Comparative Study

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Base Sequence
  • Connective Tissue Growth Factor
  • Dexamethasone / pharmacology*
  • Epithelial Cells / chemistry
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Female
  • Fibronectins / analysis
  • Fibronectins / metabolism
  • Genes, Reporter
  • Humans
  • Immediate-Early Proteins / analysis
  • Immediate-Early Proteins / biosynthesis*
  • Immediate-Early Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / analysis
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Kidney Tubules / drug effects*
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology
  • Luciferases / analysis
  • Luciferases / genetics
  • Male
  • Mice
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • Nephritis / genetics
  • Nephritis / metabolism*
  • Nephritis / pathology
  • Oligodeoxyribonucleotides, Antisense / pharmacology
  • Promoter Regions, Genetic
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Syndrome
  • Transcription, Genetic / drug effects
  • Up-Regulation

Substances

  • CCN2 protein, human
  • CCN2 protein, mouse
  • Fibronectins
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Oligodeoxyribonucleotides, Antisense
  • RNA, Messenger
  • Connective Tissue Growth Factor
  • Dexamethasone
  • Luciferases