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: Maki Urushihara, Naro Ohashi, Kayoko Miyata, Ryousuke Satou, Omar W Acres, Hiroyuki Kobori
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 57 Issue 3 Pg. 586-93 (Mar 2011) ISSN: 1524-4563 [Electronic] United States
• PMID: 21282555 (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)