Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGF beta-1 signaling

Author(s)

Papadimitriou, Alexandros ^[1] ; Peixoto, Elisa B. M. I. ^[1] ; Silva, Kamila C. ^[1] ; Lopes de Faria, Jacqueline M. ^[1] ; Lopes de Faria, Jose B. ^[1]

Affiliation

^[1] Univ Estadual Campinas, Unicamp, Fac Med Sci, Renal Pathophysiol Lab, BR-13084971 Campinas, SP - Brazil

• Document type: Journal article
• Source: JOURNAL OF NUTRITIONAL BIOCHEMISTRY; v. 25, n. 7, p. 773-784, JUL 2014.
• Web of Science Citations: 23

Abstract

The aims of the present study were to investigate, in diabetes mellitus (DM), the mechanism of NOX4 up-regulation, its link with 5' adenosine monophosphate-activated protein kinase (AMPK) inactivation and transforming growth factor (TGF) beta-1 signaling in determining the accumulation of kidney extracellular matrix (ECM), and the possible action of cocoa enriched with polyphenols (CH) in these events. After 16 weeks of DM, spontaneously hypertensive rats showed increased kidney TGF beta-1 levels and expression of phosphorylated smad2, collagen IV and fibronectin in parallel with elevated NOX4 expression and reduced phosphorylated AMPK. CH treatment in diabetic rats prevented all of these abnormalities. In immortalized human mesangial cells exposed to high glucose (HG), or TGF beta-1, CH, nicotinamide adenine dinucleotide phosphate blacker, or silencing NOX4 ameliorated enhanced phosphorylated smad2 and collagen IV. Reduction in phosphorylated AMPK induced by HG or TGF beta-1 was ameliorated by CH or activation of AMPK, which reduced phosphorylation of smad2 and collagen IV via reduction in NOX4 expression. The effects of CH were abolished by AMPK blockade. These results suggest that inactivation in AMPK leads to NOX4 up-regulation, activation of TGF beta-1 signaling and increased ECM accumulation. Additionally, increased TGF-beta 1 per se leads to the amplification of ECM production by reducing AMPK and promoting the activation of NOX4. It is suggested that the activation of AMPK by CH followed by reduction in NOX4/ TGF beta-1 signaling may have a therapeutic potential in diabetic nephropathy. Crown Copyright (C) 2014 Published by Elsevier Inc. All rights reserved. (AU)

• FAPESP's process: 12/22452-8 - Can theobromine stimulate SIRT1 (silent information regulator 1) and reduce Diabetes-associated oxidative stress and renal fibrosis?
• Grantee: Jose Butori Lopes de Faria
• Support type: Regular Research Grants
• FAPESP's process: 08/57560-0 - Effects of green tea (Camellia sinensis), cocoa and nitric oxide donor on diabetic nephropathy and retinopathy: contribution of the reduction of oxidative stress and inflammation and elevation of nitric oxide
• Grantee: Jose Butori Lopes de Faria
• Support type: Research Projects - Thematic Grants