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Osteopontin expressed by renal tubular epithelium mediates interstitial monocyte infiltration in rats
H Okada1, K Moriwaki, R Kalluri
1Department of Nephrology, Saitama Medical College, Saitama 350-04, Japan.
Abstract:
In this study, we have shown that intravenously administered antisense oligodeoxynucleotide (ODN) was demonstrated to be taken up by tubular epithelium, after which it blocked mRNA expression of target genes in normal and nephritic rats. Therefore, we injected osteopontin (OPN) antisense ODN to Goodpasture syndrome (GPS) rats every second day between days 27 and 35, the time when renal OPN expression increased and interstitial monocyte infiltration was aggravated. In parallel to blockade of tubular OPN expression, this treatment significantly attenuated monocyte infiltration and preserved renal plasma flow in GPS rats at day 37, compared with sense ODN-treated and untreated GPS rats. No significant changes were observed in OPN mRNA level by RT-PCR and histopathology of the glomeruli after ODN treatment, which was compatible with an absence of differences in the urinary protein excretion rate. In conclusion, OPN expressed by tubular epithelium played a pivotal role in mediating peritubular monocyte infiltration consequent to glomerular disease.
Insights
Intravenously administered antisense oligodeoxynucleotide (ODN) blocked kidney osteopontin (OPN) expression in rats. This treatment reduced monocyte infiltration and preserved renal plasma flow in Goodpasture syndrome (GPS) rats.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Glomerular disease progression involves increased renal osteopontin (OPN) expression.
- Tubular epithelial cells are a source of OPN in kidney disease.
- Monocyte infiltration exacerbates kidney damage in Goodpasture syndrome (GPS).
Purpose of the Study:
- To investigate the therapeutic potential of blocking OPN expression in tubular epithelium.
- To assess the effect of OPN antisense oligodeoxynucleotide (ODN) on monocyte infiltration and renal function in a GPS rat model.
Main Methods:
- Intravenous administration of OPN antisense ODN in GPS rats.
- Monitoring OPN mRNA expression, monocyte infiltration, and renal plasma flow.
- Comparison with sense ODN-treated and untreated GPS rats.
Main Results:
- Antisense ODN was taken up by tubular epithelium and blocked OPN mRNA expression.
- Treatment significantly attenuated monocyte infiltration and preserved renal plasma flow.
- No significant changes in glomerular histopathology or urinary protein excretion were observed.
Conclusions:
- OPN expressed by tubular epithelium plays a key role in mediating peritubular monocyte infiltration.
- Targeting tubular OPN expression may be a therapeutic strategy for glomerular diseases.