Role of AMP-Activated Protein Kinase in Renal Lipid Accumulation in Obesity-Induced Chronic Kidney Disease. Benefits of an Endurance Exercise Training in Mice

Background: The increased incidence of obesity in Western countries is largely due to a combination of sedentary lifestyle, associated with a high caloric intake and a lack of exercise. Furthermore, systematic reviews and meta-analysis demonstrated that obesity serves as an independent predictor of new-onset chronic kidney disease (CKD). Excessive caloric intake is related to lipid accumulation in adipose tissues but also ectopic lipid depositions in non-adipose tissues, leading to deleterious cellular responses. Our previous work demonstrated that in mice such ectopic depositions occur in the kidney following a high-fat diet (HFD), particularly in proximal tubular cells (PTC), leading to tubular cell structure impairments, inflammation and fibrosis. This was cor
AbstractsNephron 2018;139:83-111 DOI: 10.1159/000488293
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related to a reduced activity of AMP-activated Protein Kinase (AMPK), a ubiquitous heterotrimeric enzyme that is considered a major energy sensor and a master regulator in cells. Aim: This work determined for the first time the potential beneficial effect of endurance exercise training (EET) in long-term obese mice on renal lipotoxycity. Particularly, AMPK activity and lipid metabolism in isolated PTC was investigated. Methods: A mouse model presenting long term HFD-induced CKD has been used. The impact of EET has been tested after 12 weeks on diet in already obese mice using a treadmill. During the protocol, mice were placed into metabolic cages for 24 h-urine collection. Metabolic profiles regarding glucose and lipid metabolism were determined in urine and plasma samples. In addition, renal function was evaluated. Western blot, ELISA and RT-qPCR were used in kidney tissue and isolated PTC to delineate the AMPK pathway and key markers in lipid metabolism. This includes fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) to investigate the lipogenesis pathway and canityl palmitoyltransferase 1 (CPT-1) to investigate the β-oxidation pathway. Results: Mice fed a HFD exhibited a significant increase in body weight combined to increases in plasma levels of NEFA, triglycerides and cholesterol. Moreover, they also developed insulin resistance. ETT showed body weight stabilization and beneficial effects on plasma lipid profile in HFD mice. In addition, hyperglycaemia and insulin resistance were also clearly improved by exercise. Regarding the renal function, measurement of albuminuria and histological analysis suggested a more disparate result. Indeed, two populations were observed. A proportion of HFD mice submitted to EET showed positive effect on renal function along with an increase of AMPK activity while the second did not. Similar data were observed regarding ACC and FAS expression. Conclusions: These results suggest that EET leads to beneficial effects to obesity-related metabolic disorders and to some extend in kidney in mice fed a HFD. This ongoing study gives us encouraging sets of data that will be further explored in order to better characterize the impact of EET on HFD-induced CKD.