AMPK ACTIVATION AMELIORATES KIDNEY VASCULAR DYSFUNCTION, OXIDATIVE STRESS AND INFLAMMATION IN OBESITY.

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Obesity is a risk factor for the development of chronic kidney disease independent of diabetes, hypertension and other comorbidities. Obesity-associated nephropathy has been linked to dysregulation of the cell energy sensor AMP-activated protein kinase (AMPK). We aimed here to assess whether impairment of AMPK activity may cause renal arterial dysfunction in obesity and to evaluate the therapeutic potential of AMPK activation in the kidney.The effects of the AMPK activator A769662 were assessed on intrarenal arteries dissected out from ob/ob mice and obese Zucker rats kidney and then mounted in microvascular myographs. Superoxide and hydrogen peroxide production were measured by chemiluminescence and fluorescence, respectively, and protein expression was analyzed by Western blotting.Endothelium-dependent vasodilation and PI3K/Akt/eNOS pathway were impaired in preglomerular arteries from genetically obese rats and mice, along with impaired arterial AMPK activity and blunted relaxations induced by the AMPK activator A769662. Acute ex vivo exposure to A769662 restored endothelial function and enhanced activity of PI3K/Akt/eNOS pathway in obese rats, while in vivo treatment with A769662 improved metabolic state and ameliorated endothelial dysfunction, reduced inflammatory markers and vascular oxidative stress in renal arteries and restored redox balance in renal cortex of obese mice.These results demonstrate that AMPK dysregulation underlies obesity-associated kidney vascular dysfunction and activation of AMPK improves metabolic state, protects renal endothelial function and exerts potent vascular antioxidant and anti-inflammatory effects. The beneficial effects of vascular AMPK activation might represent a promising therapeutic approach for the treatment of obesity-related- kidney injury.

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Authors: Claudia Rodríguez, Ana Sánchez, Javier Sáenz-Medina, Mercedes Muñoz, Medardo Hernández, Miguel López, Luis Rivera, Cristina Contreras, Dolores Prieto