Lipidomic Analysis of Kidney Tissue ina High-Fat Diet Model: A Key Role of AMPK in Lipid Content and Storage.

Background: Lipids may contribute to renal cell toxicity. AMP-activated protein kinase (AMPK) is an important energy sensor that may play a critical role in regulating the chronic cellular response to lipid excess. Methods: To evaluate the role of AMPK, male C57BL/6J mice were randomized to a standard diet, a High Fat Diet (HFD) or a HFD + AICAR (AMPK activator) for 14 weeks. A comprehensive lipidomic approach was combined with renal functional and structural studies along with electron microscopy (EM). Results: Mice given the HFD showed renal hypertrophy and impaired renal function. Evidence of proximal tubule injury was observed with the presence of enlarged clear vacuoles, and multilaminar inclusions concurrently with an increase of tissue lipid content and a decrease of autophagy. The margins of the clear vacuoles were positive for the endolysosomal marker, LAMP1, suggesting lysosome dysfunction. Characterization of multilaminar inclusions by EM revealed that these contained onion skin-like accumulations of phospholipids. AMPK activation reversed the clinical and structural effects of HFD. To further determine the role of AMPK, we performed an analysis of lipid species by quantitative mass spectrometry to explore the connections between lipid metabolism and biochemical pathways. Lipidomic analysis revealed that HFD significantly affected eicosanoid metabolism, involving arachidonic acid, eicosapentaenoic acid (EPA) and docasahexaenoic acid (DHA), an effect that was modulated by AICAR treatment. Conclusions: These findings reveal that HFD is a potent source of renal damage. There is likely a contribution of lysosomal dysfunction and lipid species alteration that results in the changes observed. A novel role of AMPK was demonstrated to normalize the changes in renal lipid content despite chronic exposure to lipid challenge. The activation of AMPK may be a potential strategy to improve altered lipid metabolism in HFD-induced chronic kidney disease.