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

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Abstract
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.