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.
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.
Authors: Monica M Reinholz; Shawn P Zinnen; Amylou C Dueck; David Dingli; Gregory G Reinholz; Leslie A Jonart; Kathleen A Kitzmann; Amy K Bruzek; Vivian Negron; Abdalla K Abdalla; Bonnie K Arendt; Anthony J Croatt; Luis Sanchez-Perez; David P Sebesta; Harri Lönnberg; Toshiyuki Yoneda; Karl A Nath; Diane F Jelinek; Stephen J Russell; James N Ingle; Thomas C Spelsberg; Henry B F Hal Dixon; Alexander Karpeisky; Wilma L Lingle Journal: Bone Date: 2010-03-15 Impact factor: 4.398
Authors: Raj Munshi; Ali Johnson; Edward D Siew; T Alp Ikizler; Lorraine B Ware; Mark M Wurfel; Jonathan Himmelfarb; Richard A Zager Journal: J Am Soc Nephrol Date: 2010-11-11 Impact factor: 10.121
Authors: Julio P Juncos; Joseph P Grande; Narayana Murali; Anthony J Croatt; Luis A Juncos; Robert P Hebbel; Zvonimir S Katusic; Karl A Nath Journal: Am J Pathol Date: 2006-07 Impact factor: 4.307
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Authors: Michal J Tracz; Julio P Juncos; Joseph P Grande; Anthony J Croatt; Allan W Ackerman; Zvonimir S Katusic; Karl A Nath Journal: Am J Pathol Date: 2008-11-06 Impact factor: 4.307