Addition of Angiotensin II Type 1 Receptor Blocker to CCR2 Antagonist Markedly Attenuates Crescentic Glomerulonephritis
| Autor: | Kayoko Miyata, Hiroyuki Kobori, Omar W. Acres, Maki Urushihara, Ryousuke Satou, Naro Ohashi |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Anti-Glomerular Basement Membrane Disease Receptors CCR2 Glomerular Mesangial Cell Blood Pressure Enzyme-Linked Immunosorbent Assay Kidney urologic and male genital diseases Rats Inbred WKY Article Renin-Angiotensin System Transforming Growth Factor beta1 Internal medicine Renin–angiotensin system Internal Medicine medicine Animals Receptor Chemokine CCL2 Cell Proliferation Analysis of Variance Reverse Transcriptase Polymerase Chain Reaction urogenital system Chemistry Angiotensin II Macrophages Monocyte Kidney metabolism medicine.disease Immunohistochemistry female genital diseases and pregnancy complications Rats Disease Models Animal medicine.anatomical_structure Endocrinology Angiotensin II Type 1 Receptor Blockers Nephritis hormones hormone substitutes and hormone antagonists |
| Zdroj: | Hypertension. 57:586-593 |
| ISSN: | 1524-4563 0194-911X |
| DOI: | 10.1161/hypertensionaha.110.165704 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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