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Evidence for a Role of Transforming Growth Factor (TGF)-ß1 in the Induction of Postglomerular Albuminuria in Diabetic Nephropathy

Amelioration by Soluble TGF-ß Type II Receptor

From the Department of Medicine, Program in Membrane Biology and Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

Address correspondence and reprint requests to Leileata M. Russo, PhD, Program in Membrane Biology, Division of Nephrology, Massachusetts General Hospital/Harvard Medical School, Simches Research Center, 185 Cambridge St., Rm 8100, Boston, MA 02114. E-mail: leileata.russo{at}receptor.mgh.harvard.edu

Abbreviations: BCA, bicinchoninic acid protein assay; BMP7, bone morphogenic protein 7; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; IRPT, immortalized rat proximal tubule; RAS, renin-angiotensin system; sTßRII.Fc, soluble human transforming growth factor-ß type II receptor; STZ, streptozotocin; TGF-ß, transforming growth factor-ß

Transforming growth factor-ß (TGF-ß) 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-ß1 binding molecule, the soluble human TGF-ß type II receptor (sTßRII.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-ß1 disrupted albumin uptake (P < 0.001 vs. control), an inhibition significantly reversed by the use of the sTßRII.Fc (1,200 pmol/l). In vivo studies demonstrated that treatment with sTßRII.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 sTßRII.Fc treatment (P < 0.001 for diabetic vs. treated). These changes occurred independently of changes in blood glucose levels. This study demonstrates that the sTßRII.Fc is a potential new agent for the treatment of fibrosis and albuminuria in diabetic nephropathy and may reduce albuminuria by reducing TGF-ß1–induced disruptions of renal proximal tubule cell uptake of albumin.

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