Activation of AMP kinase ameliorates kidney vascular dysfunction, oxidative stress and inflammation in rodent models of obesity

Background and Purpose Obesity is a risk factor for the development of chronic kidney disease independent of diabetes, hypertension and other co-morbidities. Obesity-associated nephropathy is linked to dysregulation of the cell energy sensor AMP-activated protein kinase (). We aimed here to assess whether impairment of AMPK activity may cause renal arterial dysfunction in obesity and to evaluate the therapeutic potential of activating renal AMPK. Experimental Approach Effects of the AMPK activator were assessed on intrarenal arteries isolated from ob/ob mice and obese Zucker rats and then mounted in microvascular myographs. Superoxide and hydrogen peroxide production were measured by chemiluminescence and fluorescence, respectively, and protein expression was analysed by western blotting. Key Results 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, whereas 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. Conclusion and Implications 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 to the treatment of obesity-related kidney injury.

Automated summary

Obesity-induced dysregulation of AMPK activity is the underlying cause of kidney vascular dysfunction, and activation of AMPK improves metabolic state, protects renal endothelial function, and exerts potent vascular antioxidant and anti-inflammatory effects.