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

Osteopontin is a macrophage adhesive protein that is expressed by renal tubules in tubulointerstitial disease.

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.

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.

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.