Evidence for a role of transforming growth factor (TGF)-β1 in the induction of postglomerular albuminuria in diabetic nephropathy: Amelioration by soluble TGF-β type II receptor

Abstract

Transforming growth factor-β (TGF-β) has previously been implicated in the progression of diabetic nephropathy, including the onset of fibrosis and albuminuria. Here we report for the first time the use of a high-affinity TGF-β1 binding molecule, the soluble human TGF-β type II receptor (sTβRII.Fc), in the treatment of diabetic nephropathy in 12-week streptozotocin-induced diabetic Sprague-Dawley rats. In vitro studies using immortalized rat proximal tubule cells revealed that 50 pmol/l TGF-β1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sTβRII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sTβRII.Fc reduced urinary albumin excretion by 36% at 4 weeks, 59% at 8 weeks (P < 0.001), and 45% at 12 weeks (P < 0.01 for diabetic vs. treated). This was correlated with an increase in megalin expression (P < 0.05 for diabetic vs. treated) and a reduction in collagen IV expression following sTβRII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sTβRII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-β1-induced disruptions of renal proximal tubule cell uptake of albumin. © 2007 by the American Diabetes Association.