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

• Published in: Diabetes care Vol. 29; no. 12; pp. 2670 - 2675
• Main Authors: LANGHAM, Robyn G, CORDONNIER, Daniel J, KELLY, Darken J, PINEL, Nicole, GOW, Renae M, ZAOUI, Phillipe, YUAN ZHANG, GILBERT, Richard E
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.12.2006
• Subjects: ACE inhibitors; Adult; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Associated diseases and complications; Biological and medical sciences; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Diabetic Nephropathies - genetics; diabetic nephropathy; DNA Primers; dosage; Dosage and administration; dose response; drug therapy; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; enzyme inhibition; enzyme inhibitors; Female; gene expression; Gene Expression Regulation - drug effects; Genetic aspects; human diseases; Humans; hypoglycemic agents; Kidney; Kidneys; Male; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; noninsulin-dependent diabetes mellitus; peptidyl-dipeptidase A; Perindopril - therapeutic use; Phosphorylation; Polymerase Chain Reaction; renal function; renin-angiotensin system; RNA - genetics; RNA - isolation & purification; signal transduction; Smad2 Protein - genetics; transforming growth factor beta; Transforming Growth Factor beta - genetics; Transforming growth factors; Urinary system involvement in other diseases. Miscellaneous; Canada; Endocrinopathy; Kidney disease; Human; Urinary system disease; Enzyme; Transforming growth factor β; Diabetes mellitus; Enzyme inhibitor; Peptidases; Concomitant disease; Peptidyl-dipeptidase A; Hydrolases; Peptidyl-dipeptidases; Complication; Diabetic nephropathy; Perindopril; ACE inhibitor
• ISSN: 0149-5992
• DOI: 10.2337/dc06-0911

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. 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). 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. 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.