Renal hemodynamic, inflammatory, and apoptotic responses to lipopolysaccharide in HO-1-/- mice

Am J Pathol. 2007 Jun;170(6):1820-30. doi: 10.2353/ajpath.2007.061093.

Abstract

Lipopolysaccharide (LPS) induces the stress-responsive gene heme oxygenase-1 (HO-1). The present study examined the significance of HO-1 in response to LPS. In HO-1(-/-) mice, as compared with HO-1(+/+) mice, LPS provoked a greater reduction in glomerular filtration rate and renal blood flow, increased renal cytokine expression, and increased activation of nuclear factor (NF)-kappaB. Conversely, HO-1-overexpressing renal epithelial cells, exposed to LPS, exhibited a blunted activation of NF-kappaB and less phosphorylation of its inhibitor, IkappaB. In HO-1(-/-) mice, as compared with HO-1(+/+) mice, LPS provoked markedly greater elevations in serum levels of Th1 cytokines, Th2 cytokines, chemokines, and cytokines that stimulate bone marrow progenitors. The liver, a major source of serum cytokines, showed an increased activation of NF-kappaB in LPS-treated HO-1(-/-) mice. In addition, LPS provoked widespread apoptosis of immune cells in the spleen and thymus in HO-1(-/-) mice but not in HO-1(+/+) mice. We conclude that HO-1 deficiency exhibits a heightened and dysregulated inflammatory response to LPS accompanied by greater impairment in renal hemodynamic response and widespread apoptosis of immune cells. Because polymorphisms in the HO-1 gene with diminished HO activity predispose to human disease, we speculate that our findings may be relevant to the clinical outcome in patients with sepsis syndromes.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Chemokines / immunology
  • Cytokines / immunology
  • Female
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Inflammation / immunology*
  • Kidney* / drug effects
  • Kidney* / immunology
  • Kidney* / metabolism
  • Kidney* / pathology
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology*
  • Male
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism
  • Protein Array Analysis
  • Spleen / cytology
  • Spleen / metabolism
  • Thymus Gland / cytology
  • Thymus Gland / metabolism

Substances

  • Chemokines
  • Cytokines
  • Lipopolysaccharides
  • NF-kappa B
  • Heme Oxygenase-1