RGD Reference Report - Involvement of renal tubular Toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus. - Rat Genome Database

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Involvement of renal tubular Toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus.

Authors: Benigni, A  Caroli, C  Longaretti, L  Gagliardini, E  Zoja, C  Galbusera, M  Moioli, D  Romagnani, P  Tincani, A  Andreoli, L  Remuzzi, G 
Citation: Benigni A, etal., Arthritis Rheum. 2007 May;56(5):1569-78.
RGD ID: 7246911
Pubmed: PMID:17469139   (View Abstract at PubMed)
DOI: DOI:10.1002/art.22524   (Journal Full-text)

OBJECTIVE: Toll-like receptor 9 (TLR-9), a receptor for CpG DNA, has been implicated in the activation of immune cells in lupus. We undertook this study to determine whether the expression of TLR-9 in resident renal cells in lupus nephritis is related to the development of tubulointerstitial injury. METHODS: TLR-9 was analyzed in selectively retrieved renal tissue from (NZB x NZW)F1 mice at different stages of disease by laser capture microdissection combined with real-time quantitative reverse transcriptase-polymerase chain reaction, and in renal biopsy specimens from lupus nephritis patients by immunohistochemistry. We investigated for the molecular component responsible for TLR-9 activation by cultured proximal tubular cells in serum from patients with lupus. RESULTS: Renal tissue from NZB x NZW mice displayed robust TLR-9 expression localized to proximal tubular cells. TLR-9 levels correlated with proteinuria and tubulointerstitial injury to the extent that a cyclin-dependent kinase inhibitor, while reducing proteinuria and renal structural damage, prevented tubular TLR-9 generation in lupus mice. Consistently, exaggerated TLR-9 staining was found in proximal tubular cells of lupus patients, which correlated with tubulointerstitial damage. DNA-containing immune complexes purified from sera of patients with lupus induced TLR-9 in cultured proximal tubular cells. This was prevented by CCGG-rich short oligonucleotides, specific antagonists of CpG DNA, indicating that the DNA component of immune complexes was required for TLR-9 stimulation. CONCLUSION: These findings suggest that tubular TLR-9 activation has a pathogenetic role in tubulointerstitial inflammation and damage in experimental and human lupus nephritis, and they indicate a novel target for future therapies.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
lupus nephritis severityISOTlr9 (Mus musculus)7246911; 7246911mRNA and protein:increased expression:kidney (mouse) RGD 
lupus nephritis severityIEP 7246911mRNA and protein:increased expression:kidney (mouse) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Tlr9  (toll-like receptor 9)

Genes (Mus musculus)
Tlr9  (toll-like receptor 9)

Genes (Homo sapiens)
TLR9  (toll like receptor 9)


Additional Information