Evidence for a Role of Transforming Growth Factor (TGF)-β1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

Abstract

Transforming growth factor-beta (TGF-beta) 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-beta1 binding molecule, the soluble human TGF-beta type II receptor (sTbetaRII.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-beta1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sTbetaRII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sTbetaRII.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 sTbetaRII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sTbetaRII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-beta1-induced disruptions of renal proximal tubule cell uptake of albumin.