Effects of Elamipretide on Autophagy in Renal Cells of Pigs with Metabolic Syndrome.

Autophagy eliminates excessive nutrients and maintains homeostasis. Obesity and metabolic syndrome (MetS) dysregulate autophagy, possibly partly due to mitochondria injury and inflammation. Elamipretide (ELAM) improves mitochondrial function. We hypothesized that MetS blunts kidney autophagy, which ELAM would restore. Domestic pigs were fed a control or MetS-inducing diet for 16 weeks. During the 4 last weeks, MetS pigs received subcutaneous injections of ELAM (0.1 mg/kg/day, MetS + ELAM) or vehicle (MetS), and kidneys were then harvested to measure protein expression of autophagy mediators and apoptosis. Systemic and renal venous levels of inflammatory cytokines were measured to calculate renal release. The function of isolated mitochondria was assessed by oxidative stress, energy production, and pro-apoptotic activity. MetS slightly downregulated renal expression of autophagy mediators including p62, ATG5-12, mTOR, and AMPK vs. control. Increased mitochondrial H2O2 production accompanied decreased ATP production, elevated apoptosis, and renal fibrosis. In MetS + ELAM, mito-protection restored autophagic protein expression, improved mitochondrial energetics, and blunted renal cytokine release and fibrosis. In vitro, mitoprotection restored mitochondrial membrane potential and reduced oxidative stress in injured proximal tubular epithelial cells. Our study suggests that swine MetS mildly affects renal autophagy, possibly secondary to mitochondrial damage, and may contribute to kidney structural damage in MetS.

Renal Cellular Autophagy in Obesity: Boon or Bane?

Obesity is a growing human health concern worldwide and imposes adverse effects on many cell types and organ systems, including the kidneys. Obesity interferes with various cellular processes by increasing lipid accumulation and oxidation, insulin resistance, and inflammation. Autophagy is an important cellular process to maintain hemostasis and preserve resources, but might be altered in obesity. Interestingly, experimental studies have shown either an increase or a decrease in the rate of autophagy, and accumulation of byproducts and mediators of this cascade in kidneys of obese individuals. Hence, whether autophagy is beneficial or detrimental under these conditions remains unresolved. This review summarizes emerging evidence linking superfluous fat accumulation to alterations in autophagy. Elucidating the role of autophagy in the pathogenesis and complications of obesity in the kidney might help in the identification of therapeutic targets to prevent or delay the development of chronic kidney disease in obese subjects. Autophagy, kidney, obesity, lipids.