Renal enlargement is a characteristic feature of diabetes in humans and experimental animals that may predict subsequent renal disease. The biological processes involved in diabetes-related kidney growth are complex and involve changes in extracellular matrix, cell hypertrophy and hyperplasia. Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix protein with anti-adhesive, antiproliferative and matrix remodeling properties. We examined kidney SPARC gene expression and protein content in early experimental diabetes. By Northern blot analysis, kidney SPARC mRNA fell in diabetic animals at day 1 to 40 ± 15% of controls levels (mean ± SEM, P < 0.01), to 42% ± 11% on day 3 (P < 0.01) with a further decrease at day 7 to 29 ± 7% (P < 0.001). In situ hybridization demonstrated SPARC mRNA within glomeruli, renal interstitial cells and in blood vessels but not in tubular epithelial cells. SPARC mRNA was decreased in diabetic rats without a change in the pattern of distribution. By immunofluorescence, SPARC protein was detected in glomeruli and tubular basement membrane. Diabetes was associated with a decrease in SPARC protein at both sites. These data demonstrate that the onset of diabetes-related kidney growth is associated with a reduction in SPARC mRNA and protein. In the context of the known biological actions of SPARC, the findings in the present study implicate this matrix protein in the pathogenesis of diabetes related kidney growth.