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Transforming Growth Factor-ß in Human Diabetic Nephropathy

Effects of ACE inhibition

¹ University of Melbourne Department of Medicine, St. Vincent’s Hospital, Melbourne, Australia
² Department of Nephrology, St. Vincent’s Hospital, Melbourne, Australia
³ Centre Hospitalier Universitaire de Grenoble, Grenoble, France
⁴ Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada

Address correspondence and reprint requests to Robyn G. Langham, MD, PhD, Associate Professor of Medicine, Department of Nephrology, St. Vincent’s Hospital, 41 Victoria Parade, Fitzroy, Victoria 3065, Australia. E-mail: rlangham{at}medstv.unimelb.edu.au

OBJECTIVE—Studies in rodent models have suggested that reduction in renal transforming growth factor (TGF)-ß1 may underlie the renoprotective effects of the renin-angiotensin system (RAS) blockade. However, the role of the RAS blockade in abrogating TGF-ß in human disease is unknown. Accordingly, we sought to examine TGF-ß gene expression and biological activity in human renal biopsies, before and after ACE inhibition.

RESEARCH DESIGN AND METHODS—RNA was extracted from renal biopsies taken from participants in the Diabiopsies study, a randomized controlled 2-year trial of 4 mg/day perindopril versus placebo that reported a reduction in proteinuria and cortical matrix expansion in type 2 diabetic nephropathy. Biopsies taken at study entry and at 2 years were obtained in 12 patients (6 placebo and 6 taking perindopril). TGF-ß1 and its receptor mRNA were quantified by real-time PCR, and its biological activity was assessed by examining the activation of its intracellular signaling pathway (phosphorylated Smad2) and the expression TGF-ß–inducible gene H3 (ßig-H3).

RESULTS—At baseline, TGF-ß1 expression was similar in both placebo- and perindopril-treated groups and was unchanged over a 2-year period in biopsies of placebo-treated subjects. In contrast, perindopril treatment led to a substantial diminution in TGF-ß1 mRNA (mean 83% reduction, P < 0.05). Phosphorylated Smad2 immunolabeling and ßig-H3 mRNA were similarly reduced with ACE inhibition (P < 0.05) but unchanged in the placebo group. No differences were noted in the gene expression of TGF-ß receptor II in biopsies of either placebo- or perindopril-treated subjects.

CONCLUSIONS—This study demonstrates that over a 2-year period, treatment with perindopril in patients with type 2 diabetes and nephropathy leads to a reduction in both renal TGF-ß1 gene expression and its downstream activation.

Abbreviations: ßig-H3, TGF-ß–inducible gene H3 • RAS, renin-angiotensin system • TGF, transforming growth factor

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