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- Title
MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates.
- Authors
Pittock, Siobhan T.; Norby, Suzanne M.; Grande, Joseph P.; Croatt, Anthony J.; Bren, Gary D.; Badley, Andrew D.; Caplice, Noel M.; Griffin, Matthew D.; Nath, Karl A.
- Abstract
MCP-1 is up-regulated in unstressed and stressed HO-1 knockout mice: Pathophysiologic correlates. 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.
- Subjects
LABORATORY mice; OXYGENASES; BLOOD proteins; KIDNEY diseases; PATHOLOGICAL physiology; GROWTH factors; TRANSCRIPTION factors; AGE distribution; ANIMAL experimentation; BIOCHEMISTRY; COMPARATIVE studies; HEMOGLOBINS; INFLAMMATORY mediators; ISCHEMIA; KIDNEY glomerulus; PHENOMENOLOGY; RESEARCH methodology; MEDICAL cooperation; MEMBRANE proteins; MICE; OXIDOREDUCTASES; RESEARCH; PHYSIOLOGICAL stress; SURVIVAL; EVALUATION research
- Publication
Kidney International, 2005, Vol 68, Issue 2, p611
- ISSN
0085-2538
- Publication type
journal article
- DOI
10.1111/j.1523-1755.2005.00439.x