The accumulation of a large amount of plasma proteins in the urine, previously regarded as a marker of glomerular damage, is now recognized as a mediator of tubulointerstitial damage. Using an in vitro approach, several key extracellular matrix (ECM) proteins were analyzed after treatment of primary human renal proximal tubular epithelial cells with fatty acid free human albumin. We demonstrate that human albumin stimulates the accumulation of ECM proteins by proximal tubular epithelial cells through a post-transcriptional mechanism. Albumin induced a significant increase in tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2. Taken together, our data suggest that ECM protein accumulation in response to albumin resulted partly from inhibition of ECM degradation. Addition of transforming growth factor beta (TGF-β)-specific neutralizing antibody failed to alter ECM protein levels after albumin treatment, indicating that the albumin-induced increase in ECM is TGF-β independent. In conclusion, we have shown that exposure of cultured human proximal tubular cell to albumin leads to the TGF-β-independent accumulation of ECM proteins, suggesting that albumin may be a contributing factor to the progression of kidney fibrosis in proteinuric states.