MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates

Siobhan T. Pittock, Suzanne M. Norby, Joseph P. Grande, Anthony J. Croatt, Gary D. Bren, Andrew D. Badley, Noel M. Caplice, Matthew D. Griffin, Karl A. Nath

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

Background. Up-regulation of heme oxygenase-1 (HO-1) occurs in, and often confers protection to, the injured kidney. Up-regulation of monocyte chemoattractant protein-1 (MCP-1) promotes not only acute and chronic nephritides but also acute ischemic and nephrotoxic injury. The present study was stimulated by the hypothesis that expression of MCP-1 is suppressed by HO-1, and analyzed the effect of HO-1 on the expression of MCP-1 in stressed and unstressed conditions. Methods. Expression of MCP-1 and pathophysiologic correlates were examined in HO-1 knockout (HO-1-/-) and wild-type (HO-1+/+) mice in the unstressed state in young and aged mice, and following nephrotoxic and ischemic insults. Results. In unstressed HO-1-/- mice, plasma levels of MCP-1 protein were elevated, and MCP-1 mRNA expression was increased in circulating leukocytes and in the kidney. Such early and heightened up-regulation of MCP-1 was eventually accompanied by phenotypic changes in the aged kidney consistent with MCP-1, namely, proliferative changes in glomeruli, tubulointerstitial disease, and up-regulation of transforming growth factor-β1 (TGF-β1) and collagens I, III, and IV. In response to a nephrotoxic insult such as hemoglobin, MCP-1 mRNA was up-regulated in a markedly sustained manner in HO-1-/- mice. In response to a duration of ischemia that exerted little effect in HO-1+/+ mice, HO-1-/- mice exhibited higher expression of MCP-1 mRNA, enhanced activation of nuclear factor-κB (NF-κB) (the transcription factor that regulates MCP-1), markedly greater functional and structural renal injury, increased caspase-3 expression, and increased mortality. Conclusion. In the absence of HO-1, expression of MCP-1 is significantly and consistently enhanced in unstressed and stressed conditions. We speculate that the protective effects of HO-1 in injured tissue may involve, at least in part, the capacity of HO-1 to restrain up-regulation of MCP-1.

Original languageEnglish (US)
Pages (from-to)611-622
Number of pages12
JournalKidney international
Volume68
Issue number2
DOIs
StatePublished - Aug 1 2005

Keywords

  • Cytoprotection
  • Heme oxygenase-1
  • Ischemia
  • Kidney
  • Monocyte chemoattractant protein-1

ASJC Scopus subject areas

  • Nephrology

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