Osteopontin expression in progressive renal injury in remnant kidney: Roleof angiotensin II

Background. Osteopontin(OPN) is a macrophage chemotactic and adhesion molec ule and has been shown to play a role in glomerular and tubulointerstitial injury in several kidney disease models. Methods. The present study examined whether OPN expression is involved in t he progression of renal disease following subtotal (5/6) nephrectomy (STNx) in rats and whether angiotensin II (Ang II) mediates the up-regulation of renal OPN expression and macrophage accumulation in this model by administe ring valsartan, an Ang II type I (AT1) receptor antagonist, or ramipril, an angiotensin-converting enzyme (ACE) inhibitor. Results. In normal and sham-operated rat kidneys, OPN was expressed in a fe w tubules (<5%) and was absent in glomeruli. Following STNx (weeks 2 to 16) , there was substantial up-regulation of OPN mRNA and protein expression in glomeruli [2 to 12 cells/glomerular cross section (gcs)] and tubular epith elial cells (20 to 75% OPN+). The up-regulation of OPN expression was assoc iated with macrophage accumulation within the kidney, severe proteinuria, l oss of renal function. and severe histologic damage, including tubulitis an d tubulointerstitial fibrosis (all P < 0.001). Treatment with either valsar tan or ramipril completely abrogated the up-regulation of OPN mRNA and prot ein expression in glomeruli and tubules. The reduction in OPN expression wa s associated with a significant inhibition of macrophage accumulation and p rogressive renal injury (P < 0.001). Conclusion. An up-regulation of OPN expression may play a role in progressi ve renal injury following STNx. Inhibition of OPN expression may be one of the mechanisms by which Ang II blockade attenuated renal injury after renal ablation.