title: Parenteral iron treatment induces MCP-1 accumulation in plasma, normal kidneys, and in experimental nephropathy.
abstract: BACKGROUND
  Monocyte chemoattractant protein-1 (MCP-1) promotes renal inflammation, thereby contributing to acute and chronic nephropathies. Its production is stimulated by oxidative stress. Thus, this study tested whether pro-oxidant iron/carbohydrate complexes, used to treat iron deficiency, induce MCP-1 in renal/extrarenal tissues, in plasma, and in the setting of experimental nephropathy.
  
  
  METHODS
  CD-1 mice received 2 mg of intravenous iron [complexed with dextran (iron dextran), sucrose (iron sucrose), or gluconate (iron gluconate)]. Renal MCP-1 and/or its mRNA were measured 3 hours to 7 days post-iron injection. Iron effects on liver, lung, spleen, and heart MCP-1 mRNA, and on peritoneal lavage fluid MCP-1 concentrations were assessed. Iron pretreatment effects on MCP-1 levels in unilaterally obstructed kidneys vs. contralateral kidneys were determined. Finally, iron gluconate's influence on proximal tubule [human kidney-2 (HK-2)] cell MCP-1 levels was assessed.
  
  
  RESULTS
  Iron sucrose (the primary test agent) markedly increased plasma and renal MCP-1 levels. It also induced multiorgan MCP-1 mRNA increments (liver > spleen > kidney > lung > heart). Iron gluconate was more potent than iron sucrose; conversely, iron dextran had no discernible effect. The iron dextran and iron sucrose-induced renal MCP-1 mRNA increments ( approximately 4x) were persistent, lasting for at least 3 to 7 days. Iron gluconate raised MCP-1 levels in peritoneal lavage fluid. It also doubled MCP-1 in unilaterally obstructed kidneys (ureteral ligation) without altering contralateral (control kidney) MCP-1 content. Iron gluconate raised HK-2 cell MCP-1, implying a direct proximal tubule effect.
  
  
  CONCLUSIONS
  Iron sucrose and iron gluconate (but not iron dextran) can induce MCP-1 generation in renal and extrarenal tissues, possibly via transcriptional events. This may dramatically impact renal disease-induced MCP-1 increments. Finally, iron can increase peritoneal lavage fluid MCP-1 levels. Whether the above changes have implications for renal disease progression, and/or for peritoneal inflammation/peritoneal dialysis efficiency, are issues which may need to be addressed.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington 98109, USA. dzager@fhcrc.org
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zager
mesh_terms: D000208:Acute Disease; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000097:blood* / Q000235:genetics*; D005290:Ferric Compounds / Q000494:pharmacology; D000077605:Ferric Oxide, Saccharated; D015870:Gene Expression / Q000187:drug effects; D005937:Glucaric Acid; D005942:Gluconates / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007505:Iron-Dextran Complex / Q000494:pharmacology*; D007672:Kidney Cortex / Q000166:cytology / Q000502:physiology*; D007674:Kidney Diseases / Q000097:blood / Q000503:physiopathology*; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress / Q000187:drug effects; D010537:Peritoneum / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005290:Ferric Compounds; D005942:Gluconates; D012333:RNA, Messenger; D007505:Iron-Dextran Complex; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid