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Obstructive uropathy in the mouse: Role of osteopontin in interstitial fibrosis and apoptosis

1999; Elsevier BV; Volume: 56; Issue: 2 Linguagem: Inglês

10.1046/j.1523-1755.1999.00580.x

1523-1755

Vuddhidej Ophascharoensuk, Cecilia M. Giachelli, Katherine Gordon, Jeremy Hughes, Raimund Pichler, Paul A. Brown, Lucy Liaw, Rodney A. Schmidt, Stuart J. Shankland, Charles E. Alpers, William G. Couser, Richard J. Johnson,

Digestive system and related health

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-βbgr; 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-βbgr; mRNA expression in the interstitium at day 7 (by in situ hybridization) and a near significant 34% reduction in cortical TGF-βbgr; 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 function as a survival factor for renal tubulointerstitial cells.