Heme: A determinant of life and death in renal tubular epithelial cells

Luis Gonzalez-Michaca, Gianrico Farrugia, Anthony J. Croatt, Jawed Alam, Karl A. Nath

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

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 μM) 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 serumdeplete 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.

Original languageEnglish (US)
Pages (from-to)F370-F377
JournalAmerican Journal of Physiology - Renal Physiology
Volume286
Issue number2 55-2
DOIs
StatePublished - Feb 2004

Keywords

  • Apoptosis
  • Carbon monoxide
  • Cell growth
  • Iron
  • Renal injury

ASJC Scopus subject areas

  • Physiology
  • Urology

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