HOMEPRODUCTSSERVICESCOMPANYCONTACTFAQResearchDictionaryPharmaMobileSign Up FREE or Login

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.
AuthorsMaki Urushihara, Naro Ohashi, Kayoko Miyata, Ryousuke Satou, Omar W Acres, Hiroyuki Kobori
JournalHypertension (Hypertension) Vol. 57 Issue 3 Pg. 586-93 (Mar 2011) ISSN: 1524-4563 [Electronic] United States
PMID21282555 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Angiotensin II Type 1 Receptor Blockers
  • Chemokine CCL2
  • Receptors, CCR2
  • Transforming Growth Factor beta1
  • Angiotensin II
Topics
  • Analysis of Variance
  • Angiotensin II (pharmacology)
  • Angiotensin II Type 1 Receptor Blockers (pharmacology)
  • Animals
  • Anti-Glomerular Basement Membrane Disease (drug therapy, metabolism)
  • Blood Pressure (drug effects)
  • Cell Proliferation (drug effects)
  • Chemokine CCL2 (metabolism)
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Immunohistochemistry
  • Kidney (drug effects, metabolism)
  • Macrophages (drug effects, metabolism)
  • Male
  • Rats
  • Rats, Inbred WKY
  • Receptors, CCR2 (antagonists & inhibitors)
  • Renin-Angiotensin System (physiology)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transforming Growth Factor beta1 (metabolism)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!


Choose Username:
Email:
Password:
Verify Password: