title: AMPK mediates the initiation of kidney disease induced by a high-fat diet.
abstract: The mechanisms underlying the association between obesity and progressive renal disease are not well understood. Exposure to a high-fat diet decreases levels of the cellular energy sensor AMPK in many organs, including the kidney, but whether AMPK contributes to the pathophysiology of kidney disease induced by a high-fat diet is unknown. In this study, we randomly assigned C57BL/6J mice to a standard or high-fat diet. After 1 week, mice fed a high-fat diet exhibited an increase in body weight, renal hypertrophy, an increase in urine H(2)O(2) and urine MCP-1, and a decrease in circulating adiponectin levels and renal AMPK activity. Urine ACR progressively increased after 4 weeks of a high-fat diet. After 12 weeks, kidneys of mice fed a high-fat diet demonstrated a marked increase in markers of fibrosis and inflammation, and AMPK activity remained significantly suppressed. To determine whether inhibition of AMPK activity explained these renal effects, we administered an AMPK activator along with a high-fat diet for 1 week. Although AMPK activation did not abrogate the weight gain, it reduced the renal hypertrophy, urine H(2)O(2), and urine and renal MCP-1. In vitro, AMPK activation completely inhibited the induction of MCP-1 by palmitic acid in mesangial cells. In conclusion, these data suggest that the energy sensor AMPK mediates the early renal effects of a high-fat diet.
authors.affiliation: Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
authors.forename: Anne-Emilie
authors.initials: AE
authors.lastname: Declèves
authors.forename: Anna V
authors.initials: AV
authors.lastname: Mathew
authors.forename: Robyn
authors.initials: R
authors.lastname: Cunard
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000419:Albuminuria / Q000209:etiology; D000818:Animals; D015415:Biomarkers / Q000652:urine; D018932:Chemokine CCL2 / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects*; D004789:Enzyme Activation; D006943:Hyperglycemia / Q000209:etiology; D006984:Hypertrophy / Q000209:etiology; D007333:Insulin Resistance; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications / Q000201:enzymology*
chemical_list: D015415:Biomarkers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D004041:Dietary Fats; D055372:AMP-Activated Protein Kinases