Transforming growth factor-beta in human diabetic nephropathy: effects of ACE inhibition.
OBJECTIVE
Studies in rodent models have suggested that reduction in renal transforming growth factor (TGF)-beta1 may underlie the renoprotective effects of the renin-angiotensin system (RAS) blockade. However, the role of the RAS blockade in abrogating TGF-beta in human disease is unknown. Accordingly, we sought to examine TGF-beta gene expression and biological activity in human renal biopsies, before and after ACE inhibition.


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-beta1 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-beta-inducible gene H3 (betaig-H3).


RESULTS
At baseline, TGF-beta1 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-beta1 mRNA (mean 83% reduction, P < 0.05). Phosphorylated Smad2 immunolabeling and betaig-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-beta 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-beta1 gene expression and its downstream activation.
Langham
Robyn G
RG
University of Melbourne, Department of Medicine, St. Vincent's Hospital, Australia. rlangham@medstv.unimelb.edu.au
Kelly
Darren J
DJ
Gow
Renae M
RM
Zhang
Yuan
Y
Cordonnier
Daniel J
DJ
Pinel
Nicole
N
Zaoui
Phillipe
P
Gilbert
Richard E
RE
D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D020913:Perindopril / Q000627:therapeutic use*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D051899:Smad2 Protein / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*
D000806:Angiotensin-Converting Enzyme Inhibitors; D017931:DNA Primers; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D012313:RNA; D020913:Perindopril