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- Title
Obstructive uropathy in the mouse: Role of osteopontin in interstitial fibrosis and apoptosis.
- Authors
Ophascharoensuk, Vuddhidej; Giachelli, Cecilia M.; Gordon, Katherine; Hughes, Jeremy; Pichler, Raimund; Brown, Paul; Liaw, Lucy; Schmidt, Rodney; Shankland, Stuart J.; Alpers, Charles E.; Couser, William G.; Johnson, Richard J.
- Abstract
Obstructive uropathy in the mouse: Role of osteopontin in interstitial fibrosis and apoptosis. Background. Osteopontin is a macrophage adhesive protein that is expressed by renal tubules in tubulointerstitial disease. Methods. To investigate the function of OPN, we induced tubulointerstitial disease in OPN null mutant (OPN-/- ) and wild-type (OPN+/+ ) mice by unilateral ureteral ligation. Tissue was analyzed for macrophages (ED-1), types I and IV collagen deposition, TGF-β expression, and for tubular and interstitial cell apoptosis. Results. Obstructed kidneys from both OPN-/- and OPN+/+ mice developed hydronephrosis, tubular atrophy, interstitial inflammation and fibrosis. OPN was absent in OPN-/- kidneys but was increased in obstructed OPN+/+ kidneys. Macrophage influx, measured by computer-assisted quantitative immunostaining, was less in OPN-/- mice compared to OPN+/+ mice at day 4 (threefold, P < 0.02), day 7 (fivefold, P < 0.02), but not at day 14. Interstitial deposition of types I and IV collagen were also two- to fourfold less in obstructed OPN-/- kidneys (P < 0.02). There was also a reduction of TGF-β mRNA expression in the interstitium at day 7 (by in situ hybridization) and a near significant 34% reduction in cortical TGF-β activity (P = 0.06) compared to obstructed OPN+/+ kidneys at day 14. Obstructed kidneys from OPN-/- mice also had more interstitial and tubular apoptotic cells (TUNEL assay) compared to obstructed OPN+/+ mice at all time points. The ability of OPN to act as a cell survival factor was also documented by showing that the apoptosis of serum-starved NRK52E renal epithelial cells was markedly enhanced in the presence of neutralizing anti-OPN antibody. Conclusion. OPN mediates early interstitial macrophage influx and interstitial fibrosis in unilateral ureteral obstruction. OPN may also...
- Subjects
OSTEOPONTIN; KIDNEY tubules; DISEASES
- Publication
Kidney International, 1999, Vol 56, Issue 2, p571
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1046/j.1523-1755.1999.00580.x