Theobromine increases NAD(+)/Sirt-1 activity and protects the kidney under diabetic conditions

Author(s)

Papadimitriou, Alexandros ^[1] ; Silva, Kamila C. ^[1] ; Peixoto, Elisa B. M. I. ^[1] ; Borges, Cynthia M. ^[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, Sao Paulo - Brazil

• Document type: Journal article
• Source: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY; v. 308, n. 3, p. F209-F225, FEB 1 2015.
• Web of Science Citations: 13

Abstract

Reduction in sirtuin 1 (Sirt-1) is associated with extracellular matrix (ECM) accumulation in the diabetic kidney. Theobromine may reduce kidney ECM accumulation in diabetic rats. In the current study, we aimed to unravel, under diabetic conditions, the mechanism of kidney ECM accumulation induced by a reduction in Sirt-1 and the effect of theobromine in these events. In vitro, we used immortalized human mesangial cells (iHMCs) exposed to high glucose (HG; 30 mM), with or without small interfering RNA for NOX4 and Sirt-1. In vivo, spontaneously hypertensive rats (SHR) were rendered diabetic by means of streptozotocin and studied after 12 wk. The effects of treatment with theobromine were investigated under both conditions. HG leads to a decrease in Sirt-1 activity and NAD(+) levels in iHMCs. Sirt-1 activity could be reestablished by treatment with NAD(+), silencing NOX4, and poly (ADP-ribose) polymerase-1 (PARP-1) blockade, or with theobromine. HG also leads to a low AMP/ATP ratio, acetylation of SMAD3, and increased collagen IV, which is prevented by theobromine. Sirt-1 or AMPK blockade abolished these effects of theobromine. In diabetic SHR, theobromine prevented increases in albuminuria and kidney collagen IV, reduced AMPK, elevated NADPH oxidase activity and PARP-1, and reduced NAD(+) levels and Sirt-1 activity. These results suggest that in diabetes mellitus, Sirt-1 activity is reduced by PARP-1 activation and NAD(+) depletion due to low AMPK, which increases NOX4 expression, leading to ECM accumulation mediated by transforming growth factor (TGF)-beta 1 signaling. It is suggested that Sirt-1 activation by theobromine may have therapeutic potential for diabetic nephropathy. (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 Opportunities: 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 Opportunities: Research Projects - Thematic Grants