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

Michal J. Tracz, Julio P. Juncos, Joseph Peter Grande, Anthony J. Croatt, Allan W. Ackerman, Govindarajan Rajagopalan, Keith L Knutson, Andrew David Badley, Matthew D. Griffin, Jawed Alam, Karl A Nath

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48 Scopus citations

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)-κB. Conversely, HO-1-overexpressing renal epithelial cells, exposed to LPS, exhibited a blunted activation of NF-κB and less phosphorylation of its inhibitor, IκB. 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-κB 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.

Original languageEnglish (US)
Pages (from-to)1820-1830
Number of pages11
JournalAmerican Journal of Pathology
Volume170
Issue number6
DOIs
StatePublished - Jun 2007

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ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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