Increase in AMPK brought about by cocoa is renoprotective in experimental diabetes mellitus by reducing NOX4/TGFβ-1 signaling.
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) ß-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 TGFβ-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 TGFβ-1, CH, nicotinamide adenine dinucleotide phosphate blocker, or silencing NOX4 ameliorated enhanced phosphorylated smad2 and collagen IV. Reduction in phosphorylated AMPK induced by HG or TGFβ-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 TGFβ-1 signaling and increased ECM accumulation. Additionally, increased TGF-ß1 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/TGFβ-1 signaling may have a therapeutic potential in diabetic nephropathy.
Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: alexbiochemist@gmail.com.
Alexandros
A
Papadimitriou
Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: empeixoto@gmail.com.
Elisa B M I
EB
Peixoto
Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: kamila@fcm.unicamp.br.
Kamila C
KC
Silva
Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: lopesdefariajm@gmail.com.
Jacqueline M
JM
Lopes de Faria
Renal Pathophysiology Laboratory, Investigation on Diabetes Complications, Faculty of Medical Sciences, State University of Campinas (Unicamp), Campinas, São Paulo, Brazil. Electronic address: jblfaria@gmail.com.
José B
JB
Lopes de Faria
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002099:Cacao; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003928:Diabetic Nephropathies / Q000517:prevention & control*; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000187:drug effects*; D059808:Polyphenols / Q000494:pharmacology*; D011918:Rats, Inbred SHR; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D059808:Polyphenols; D053773:Transforming Growth Factor beta1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D055372:AMP-Activated Protein Kinases
5′ adenosine monophosphate-activated protein kinase (AMPK); Cocoa enriched with polyphenols (CH); Diabetic nephropathy (DN); Extracellular matrix accumulation (ECM); Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; Transforming growth factor β-1 (TGFβ-1)