Transforming growth Factor-β in human diabetic nephropathy: Effects of ACE inhibition

Robyn G. Langham, Darren J. Kelly, Renae M. Gow, Yuan Zhang, Daniel J. Cordonnier, Nicole Pinel, Phillipe Zaoui, Richard E Gilbert

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Abstract

OBJECTIVE - Studies in rodent models have suggested that reduction in renal transforming growth factor (TGF)-β1 may underlie the renoprotective effects of the renin-angiotensin system (RAS) blockade. However, the role of the RAS blockade in abrogating TGF-β in human disease is unknown. Accordingly, we sought to examine TGF-β gene expression and biological activity in human renal biopsies, before and after ACE inhibition. RESEARCH DESIGNANDMETHODS - 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-β1 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-β-inducible gene H3 (βig-H3). RESULTS - At baseline, TGF-β1 expression was similar in both placebo- and perindopriltreated 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-β1 mRNA (mean 83% reduction, P < 0.05). Phosphorylated Smad2 immunolabeling and βig-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-β 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-β1 gene expression and its downstream activation.

Original languageEnglish
Pages (from-to)2670-2675
Number of pages6
JournalDiabetes Care
Volume29
Issue number12
DOIs
Publication statusPublished - Dec 2006
Externally publishedYes

Cite this

Langham, R. G., Kelly, D. J., Gow, R. M., Zhang, Y., Cordonnier, D. J., Pinel, N., Zaoui, P., & Gilbert, R. E. (2006). Transforming growth Factor-β in human diabetic nephropathy: Effects of ACE inhibition. Diabetes Care, 29(12), 2670-2675. https://doi.org/10.2337/dc06-0911