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The role played by endocytosis in albumin-induced secretion of TGF-₁ by proximal tubular epithelial cells

¹South West Thames Institute for Renal Research, St. Helier Hospital, Carshalton, Surrey, United Kingdom, ²Department of Nephrology, Leicester General Hospital, Leicester, United Kingdom

Submitted 24 February 2006 ; accepted in final form 27 December 2006

Proteinuria predicts the decline of renal function in chronic kidney disease. Reducing albuminuria has been shown to be associated with a reduction in this rate of decline. Proximal tubular epithelial cells (PTECs), when exposed to albumin produce matrix proteins, proinflammatory and profibrotic cytokines like TGF-₁. Some of these effects are dependent on endocytosis of albumin by PTECs. However, conditions like diabetic nephropathy, believed to be associated with reduced albumin endocytosis, are associated with interstitial fibrosis. Moreover, megalin, the putative albumin binding receptor in PTECs, has potential signaling motifs in its cytoplasmic domain, suggesting its ability to signal in response to ligand binding from the apical surface of PTECs. Hence, we looked to see whether albumin-induced secretion of TGF-₁ by PTECs is dependent on albumin endocytosis or whether it could occur in the absence of albumin endocytosis. We studied the production of TGF-₁ in two accepted models of PTECs, opossum kidney cells and human kidney cell clone-8 cells, with widely varying degrees of endocytosis. We then studied the effect of inhibiting albumin endocytosis with various inhibitors on albumin-induced TGF-₁ secretion. Our results indicate that albumin-induced TGF-₁ secretion by PTECs does not require albumin endocytosis and therefore the mechanism for the induction of some profibrotic responses by albumin may differ from those required for some of the inflammatory responses. Moreover, we found that albumin-induced TGF-₁ secretion by PTECs is not dependent on its interaction with megalin.

megalin; receptor-associated protein; simvastatin; albuminuria