Theobromine increases NAD+/Sirt-1 activity and protects the kidney under diabetic conditions
| Autor: | Elisa B.M.I. Peixoto, José B. Lopes de Faria, Cynthia M. Borges, Kamila C. Silva, Jacqueline M. Lopes de Faria, Alexandros Papadimitriou |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty Physiology Poly (ADP-Ribose) Polymerase-1 Kidney medicine.disease_cause Diabetes Mellitus Experimental Extracellular matrix Diabetic nephropathy Sirtuin 1 Rats Inbred SHR Internal medicine medicine Animals Theobromine chemistry.chemical_classification Reactive oxygen species biology Chemistry NAD medicine.disease Rats Disease Models Animal Oxidative Stress Endocrinology medicine.anatomical_structure biology.protein NAD+ kinase Poly(ADP-ribose) Polymerases Reactive Oxygen Species Oxidative stress medicine.drug |
| Zdroj: | American Journal of Physiology-Renal Physiology. 308:F209-F225 |
| ISSN: | 1522-1466 1931-857X |
| Popis: | 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)-β1 signaling. It is suggested that Sirt-1 activation by theobromine may have therapeutic potential for diabetic nephropathy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|