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AMPK mediates the initiation of kidney disease induced by a high-fat diet
Anne-Emilie Declèves1, Anna V Mathew, Robyn Cunard
1Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA.
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.
Insights
High-fat diets harm kidneys by lowering AMPK activity, a cellular energy sensor. Activating AMPK can mitigate some diet-induced kidney damage, suggesting a key role in obesity-related renal disease.
Area of Science:
- Metabolic pathways
- Renal pathophysiology
- Obesity-related diseases
Background:
- Obesity is linked to progressive kidney disease, but underlying mechanisms remain unclear.
- High-fat diets reduce AMP-activated protein kinase (AMPK) levels in organs like the kidney.
- The role of AMPK in high-fat diet-induced kidney disease is unknown.
Purpose of the Study:
- To investigate the role of AMPK in high-fat diet-induced kidney disease.
- To determine if AMPK inhibition contributes to renal pathophysiology.
- To assess the therapeutic potential of AMPK activation in mitigating diet-induced renal damage.
Main Methods:
- C57BL/6J mice were fed standard or high-fat diets.
- Renal function, inflammation, fibrosis markers, and AMPK activity were assessed.
- AMPK activator was administered with a high-fat diet in some mice.
- In vitro studies used mesangial cells treated with palmitic acid and an AMPK activator.
Main Results:
- High-fat diet increased body weight, renal hypertrophy, urine H2O2, and MCP-1, while decreasing adiponectin and renal AMPK activity.
- AMPK activation partially reduced high-fat diet-induced renal hypertrophy, oxidative stress, and MCP-1 levels.
- In vitro, AMPK activation inhibited MCP-1 induction by palmitic acid in mesangial cells.
Conclusions:
- AMPK plays a crucial role in mediating the early renal effects of high-fat diets.
- AMPK activity is suppressed by high-fat diets, contributing to renal damage.
- AMPK activation shows potential for preventing or treating obesity-related kidney disease.
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