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

Kidney Int. 2005 Aug;68(2):611-22. doi: 10.1111/j.1523-1755.2005.00439.x.


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-beta1 (TGF-beta1) 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-kappaB (NF-kappaB) (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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Age Factors
  • Animals
  • Chemokine CCL2 / genetics*
  • Heme Oxygenase (Decyclizing) / genetics*
  • Heme Oxygenase-1
  • Hemoglobins / toxicity
  • Ischemia / mortality
  • Ischemia / pathology
  • Ischemia / physiopathology*
  • Kidney Diseases / mortality
  • Kidney Diseases / pathology
  • Kidney Diseases / physiopathology*
  • Kidney Glomerulus / pathology
  • Kidney Glomerulus / physiopathology
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Stress, Physiological / mortality
  • Stress, Physiological / pathology
  • Stress, Physiological / physiopathology*
  • Survival Rate
  • Up-Regulation


  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Hemoglobins
  • Membrane Proteins
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • Hmox1 protein, mouse