RGD Reference Report - Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis. - Rat Genome Database

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Addition of angiotensin II type 1 receptor blocker to CCR2 antagonist markedly attenuates crescentic glomerulonephritis.

Authors: Urushihara, M  Ohashi, N  Miyata, K  Satou, R  Acres, OW  Kobori, H 
Citation: Urushihara M, etal., Hypertension. 2011 Mar;57(3):586-93. Epub 2011 Jan 31.
RGD ID: 5129185
Pubmed: PMID:21282555   (View Abstract at PubMed)
PMCID: PMC3048031   (View Article at PubMed Central)
DOI: DOI:10.1161/HYPERTENSIONAHA.110.165704   (Journal Full-text)

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-beta1 (TGF-beta1), 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-beta1. 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-beta1 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-beta1 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
anti-basement membrane glomerulonephritis  ISOAgt (Rattus norvegicus)5129185; 5129185protein:increased expression:kidney and urineRGD 
anti-basement membrane glomerulonephritis  ISOAgtr1a (Rattus norvegicus)5129185; 5129185protein:increased expression:kidneyRGD 
anti-basement membrane glomerulonephritis  IEP 5129185protein:increased expression:kidney and urineRGD 
anti-basement membrane glomerulonephritis  IEP 5129185protein:increased expression:kidneyRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cytokine production  IDA 5129185 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Agt  (angiotensinogen)
Agtr1a  (angiotensin II receptor, type 1a)

Genes (Mus musculus)
Agt  (angiotensinogen)
Agtr1a  (angiotensin II receptor, type 1a)

Genes (Homo sapiens)
AGT  (angiotensinogen)
AGTR1  (angiotensin II receptor type 1)


Additional Information