| pubmed-article:14707007 | pubmed:abstractText | Heme oxygenase-1 (HO-1) and p21 influence cell fate, and genetic HO-1 overexpression upregulates p21 and confers resistance to apoptosis. The present study examined the effects of heme, a metabolite incriminated in renal injury, on sensitivity to apoptosis and cell growth in conjunction with cellular expression of HO-1 and p21. Immortalized rat proximal tubular epithelial cells (IRPTCs) were exposed to hemin (10 microM) in serum-deplete media (0.1% FBS) and in standard cell culture media (5.0% FBS). In the presence of 0.1% FBS media, hemin induced p21 through an HO-dependent, p53-independent mechanism; certain products of HO activity (iron and carbon monoxide), but not others (ferritin, apoferritin, bilirubin), recapitulated these inductive effects on p21 expression. Along with this inductive effect on HO-1 and p21, hemin worsened apoptosis, the latter exacerbated by the inhibition of HO activity and loss of p21 expression. In IRPTCs maintained in 5% FBS, hemin induced HO-dependent p21 expression, provoked cell cycle arrest, and inhibited cell growth without inducing apoptosis; this inhibitory effect of hemin on cell growth was blocked by the concomitant inhibition of HO activity and loss of p21 expression. We conclude that hemin is a potent HO-dependent inducer of p21 and that hemin increases the sensitivity to apoptosis in serum-deplete conditions and decreases cell growth in serum-replete conditions; inhibiting HO activity and concomitantly ablating p21 expression exacerbate apoptosis and reverse the growth-inhibitory actions of hemin. We suggest that these effects of heme may influence the nature of, and recovery from, ischemic and nephrotoxic insults to the kidney. | lld:pubmed |
