title: Renin-angiotensin blockade lowers MCP-1 expression in diabetic rats.
abstract: BACKGROUND
  Glomerular macrophage accumulation in diabetes implicates monocyte recruitment mechanisms in the pathogenesis of diabetic nephropathy. To test the hypothesis that overexpression of monocyte chemoattractant protein-1 (MCP-1), a monocyte chemoattractant, is attenuated by renin-angiotensin system (RAS) inhibition, we assessed expression of genes regulating monocyte transmigration in the glomeruli of diabetic rats.
  
  
  METHODS
  Competitive reverse transcription-polymerase chain reaction (RT-PCR) was used to semiquantitate mRNA expression in glomeruli harvested by sieving at serial intervals after the induction of diabetes by streptozotocin in Munich-Wistar rats. Although subject to limitations, competitive RT-PCR provides an objective measure suited to the minute quantities of RNA extractable from glomerular isolates.
  
  
  RESULTS
  Time-dependent elevation of MCP-1 expression was dramatically suppressed by treatment with the angiotensin-converting enzyme inhibitor enalapril or the AT1 receptor antagonist candesartan, and was closely associated with effects on proteinuria and glomerular macrophage number. By contrast, no sustained suppression of the cell adhesion molecules intercellular adhesion molecule-1 or vascular cell adhesion molecule-1 or the classic MCP-1 stimulators tumor necrosis factor-alpha or interleukin-1beta followed RAS inhibition, and suppression of transforming growth factor-beta1 expression was transient.
  
  
  CONCLUSIONS
  These data suggest that glomerular macrophage recruitment in experimental diabetes is largely determined by angiotensin-stimulated MCP-1 expression. We conclude that the RAS is an important regulator of local MCP-1 expression, either directly or through glomerular hemodynamic effects, and that our data strongly implicate macrophage recruitment and activation in the pathogenesis of early diabetic glomerular injury.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: V A
authors.initials: VA
authors.lastname: Luyckx
authors.forename: M
authors.initials: M
authors.lastname: Ots
authors.forename: K W
authors.initials: KW
authors.lastname: Lee
authors.forename: F
authors.initials: F
authors.lastname: Ziai
authors.forename: J L
authors.initials: JL
authors.lastname: Troy
authors.forename: B M
authors.initials: BM
authors.lastname: Brenner
authors.forename: H S
authors.initials: HS
authors.lastname: MacKenzie
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D018932:Chemokine CCL2 / Q000235:genetics*; D016207:Cytokines / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D004656:Enalapril / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006133:Growth Substances / Q000235:genetics; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000473:pathology / Q000502:physiology; D008297:Male; D011507:Proteinuria / Q000209:etiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018932:Chemokine CCL2; D016207:Cytokines; D017931:DNA Primers; D006133:Growth Substances; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D004656:Enalapril; C081643:candesartan