Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix-associated protein with antiadhesive, antiproliferative, and matrix remodeling properties. SPARC gene and protein expression were investigated after subtotal nephrectomy (STNx), a model of noninflammatory progressive renal injury. In addition, the effect of blockade of the renin-angiotensin system by the angiotensin-converting enzyme inhibitor ramipril or by the angiotensin II receptor antagonist valsartan was examined. The STNx rats developed hypertension, proteinuria, and renal impairment. These changes were associated with a 2.4-fold increase in SPARC gene expression in STNx compared with SHAM kidneys (P < 0.001). In situ hybridization revealed increased SPARC mRNA in glomeruli and interstitial cells, as well as de novo expression by tubular epithelial cells at sites of renal injury. Immunofluorescence studies confirmed concordant changes in SPARC protein. Both ramipril and valsartan ameliorated renal injury and significantly reduced SPARC overexpression in the STNx animals. The findings of the present study suggest that SPARC, in the context of its known biological actions, may influence some of the pathological features associated with significant renal mass reduction.