Insulin induces heme oxygenase-1 through the phosphatidylinositol 3-kinase/Akt pathway and the Nrf2 transcription factor in renal cells

FEBS J. 2006 Jun;273(11):2345-56. doi: 10.1111/j.1742-4658.2006.05224.x.


Heme oxygenase-1 catalyzes the breakdown of heme and is protective in models of kidney transplantation. In this study we describe the induction of heme oxygenase-1 mRNA and protein by insulin. Following treatment with insulin, a five-fold increase in heme oxygenase-1 mRNA and a four-fold increase in protein expression were observed in renal adenocarcinoma cells; insulin-induced heme oxygenase-1 expression was also demonstrated in mouse primary tubular epithelial cells. The induction of heme oxygenase-1 in renal adenocarcinoma cells was blocked by actinomycin D and cycloheximide and was abolished by the phosphatidylinositol 3-kinase inhibitor, LY294002, but not by the inactive analog LY303511. Overexpressing a dominant-negative form of Akt abrogated the heme oxygenase-1-inducing effects of insulin, whereas cells transfected with a constitutively active Akt construct demonstrated an increase in heme oxygenase-1 promoter activity and protein expression. The transcription factor NF-E2-related factor-2 was found to translocate to the nucleus following insulin treatment in a phosphatidylinositol 3-kinase-dependent manner. Pretreatment with NF-E2-related factor-2 small-interfering RNA abolished insulin-induced heme oxygenase-1 induction. Insulin was also found to activate the mitogen-activated protein kinase cascades p38 and extracellular signal-related kinase; however, inhibition of these pathways with SB202190 and PD98059 did not alter insulin-induced heme oxygenase-1 expression. Thus, insulin induces heme oxygenase-1 mRNA and protein expression in renal cells in a phosphatidylinositol 3-kinase/Akt and NF-E2-related factor-2-dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma
  • Animals
  • Cell Line, Tumor
  • Enzyme Induction
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects
  • Epithelial Cells / enzymology
  • Heme Oxygenase-1 / biosynthesis
  • Heme Oxygenase-1 / genetics*
  • Humans
  • Insulin / pharmacology*
  • Kidney Neoplasms
  • Kidney Tubules / cytology
  • Kidney Tubules / drug effects
  • Kidney Tubules / enzymology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • NF-E2-Related Factor 2 / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • RNA, Messenger / genetics
  • Transcription, Genetic


  • Insulin
  • NF-E2-Related Factor 2
  • RNA, Messenger
  • Heme Oxygenase-1
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt