title: Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis.
abstract: The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor 2 (CCR2) pathway plays a critical role in the development of antiglomerular basement membrane (anti-GBM) nephritis. We recently showed angiotensin II (Ang II) infusion in rats activated MCP-1 and transforming growth factor-β1 (TGF-β1), which in turn induced macrophage infiltration of renal tissues. This study was performed to demonstrate that combination therapy with a CCR2 antagonist (CA) and an Ang II type 1 receptor blocker (ARB) ameliorated renal injury in the anti-GBM nephritis model. An anti-GBM nephritis rat model developed progressive proteinuria and glomerular crescent formation, accompanied by increased macrophage infiltration and glomerular expression of MCP-1, angiotensinogen, Ang II, and TGF-β1. Treatment with CA alone or ARB alone moderately ameliorated kidney injury; however, the combination treatment with CA and ARB dramatically prevented proteinuria and markedly reduced glomerular crescent formation. The combination treatment also suppressed the induction of macrophage infiltration, MCP-1, angiotensinogen, Ang II, and TGF-β1 and reversed the fibrotic change in the glomeruli. Next, primary cultured glomerular mesangial cells (MCs) stimulated by Ang II showed significant increases in MCP-1 and TGF-β1 expression. Furthermore, cocultured model consisting of MCs, parietal epithelial cells, and macrophages showed an increase in Ang II-induced cell proliferation and collagen secretion. ARB treatment attenuated these augmentations. These data suggest that Ang II enhances glomerular crescent formation of anti-GBM nephritis. Moreover, our results demonstrate that inhibition of the MCP-1/CCR2 pathway with a combination of ARB effectively reduces renal injury in anti-GBM nephritis.
authors.affiliation: Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, LA 70112-2699, USA.
authors.forename: Maki
authors.initials: M
authors.lastname: Urushihara
authors.forename: Naro
authors.initials: N
authors.lastname: Ohashi
authors.forename: Kayoko
authors.initials: K
authors.lastname: Miyata
authors.forename: Ryousuke
authors.initials: R
authors.lastname: Satou
authors.forename: Omar W
authors.initials: OW
authors.lastname: Acres
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000188:drug therapy* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors*; D012084:Renin-Angiotensin System / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D018932:Chemokine CCL2; D054390:Receptors, CCR2; D053773:Transforming Growth Factor beta1; D000804:Angiotensin II