ANG II receptor blockade enhances anti-inflammatory macrophages in anti-glomerular basement membrane glomerulonephritis

Am J Physiol Renal Physiol. 2010 Apr;298(4):F870-82. doi: 10.1152/ajprenal.00374.2009. Epub 2010 Jan 13.


Macrophages are heterogeneous immune cell populations that include classically activated and alternatively activated (M2) macrophages. We examined the anti-inflammatory effect of ANG II type 1 receptor (AT(1)R) blocker (ARB) on glomerular inflammation in a rat model of anti-glomerular basement membrane (GBM) glomerulonephritis (GN). The study focused on infiltrating CD8(+) and CD4(+) cells and macrophages, as well as the heterogeneity of intraglomerular macrophages. Wistar-Kyoto rats were treated with high-dose olmesartan (3, low-dose olmesartan (0.3, or vehicle (control) 7 days before induction of anti-GBM GN. Control rats showed mainly CD8(+) cells and ED1(+) macrophages, with a few CD4(+) cells infiltrating the glomeruli. Necrotizing and crescentic glomerular lesions developed by day 7 with the increase of proteinuria. AT(1)R was expressed on CD8(+) and CD4(+) cells and on ED1(+) macrophages. Low-dose ARB had no anti-inflammatory effects in anti-GBM GN. However, high-dose ARB reduced glomerular infiltration of CD8(+) cells and ED1(+) macrophages and suppressed necrotizing and crescentic lesions by days 5 to 7 (P < 0.05). In addition, high-dose ARB reduced the numbers of ED3(+)-activated macrophages, suppressed glomerular TNF-alpha and IFN-gamma production, and downregulated M1-related chemokine and cytokines (monocyte chemoattractant protein type 1, IL-6, and IL-12). High-dose ARB also enhanced ED2(+) M2 macrophages by day 7 with upregulation of glomerular IL-4 and IL-13 and augmented CCL17, IL-1 receptor antagonist, and IL-10. We concluded that high-dose ARB inhibits glomerular inflammation by increasing the numbers of M2 macrophages and upregulation of anti-inflammatory cytokines and by suppressing M1 macrophage development with downregulation of M1-related proinflammatory cytokines.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers / pharmacology*
  • Angiotensin Receptor Antagonists*
  • Animals
  • Anti-Glomerular Basement Membrane Disease / immunology*
  • Anti-Glomerular Basement Membrane Disease / metabolism
  • Anti-Glomerular Basement Membrane Disease / pathology
  • Blood Pressure / drug effects
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / physiology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / physiology
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Imidazoles / pharmacology
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Macrophages / drug effects
  • Macrophages / physiology*
  • Male
  • Rats
  • Rats, Inbred WKY
  • Tetrazoles / pharmacology


  • Angiotensin II Type 1 Receptor Blockers
  • Angiotensin Receptor Antagonists
  • Cytokines
  • Imidazoles
  • Tetrazoles
  • olmesartan