Sustained proteinuria is an independent risk factor leading to kidney fibrosis and end-stage renal fail-ure. Over-reabsorption of filtered proteins, notably albu-min, has been proved to trigger interstitial inflammation and fibrosis in proteinuric renal disease. Cubilin, an endo-cytic receptor expressed on the renal tubular brush bor-der, is responsible for albumin reabsorption in physiologic condition. However, little is known about whether it is required for activation of tubular cells induced by albu-min overload. In this work, we investigated the change of cubilin expression and its potential role in albumin-induced up-regulation of chemokines synthesis in vivo and in vitro. Twenty-six patients with nephrotic syndrome were enrolled in this study. Proximal tubule uptake of albumin, expression of apical membrane cubilin and infiltrating cells in kidney interstitium were determined by immunocytochemistry. In vitro, the transcription of cubilin in HK2 cells after exposure to albumin was ana-lyzed by real-time PCR. Endocytosis of albumin in HK2 cells was examined by fluorescent microscope. The influ-ence of inhibition of cubilin on albumin-induced expres-sions of monocyte chemoattractant protein 1 (MCP-1) and regulated upon activation normal T-cell expressed and secreted (RANTES) was investigated by Weste blot. The intensity of luminal cubilin and tubular accu-mulation of albumin were significantly increased in nephrotic kidneys. The expression of MCP-1 and RANTES was up-regulated, and there were spatial rela-tionships in localization between these chemokines and cubilin as well as intracellular albumin in kidney tissues. Infiltration of CD-3 and ED-1-positive cells was predom-inant in tubulointerstitial areas displaying signs of increases of cubilin expression and albumin accumula-tion. In vitro, the transcription of cubilin mRNA in HK2 cells was enhanced after 24 h exposure to albumin in a dose-dependent manner. Inhibition of endocytosis of albumin by antisense cubilin nucleotide markedly reduced expression of MCP-1 and RANTES. Cubilin was required for handling a greater amount of protein in nephrotic status and albumin-induced production of MCP-1 and RANTES by renal tubular cells, which further initiated tubulointerstitial inflammation in proteinuric disease.