Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis.
Albuminuria is associated with metabolic syndrome and diabetes. It correlates with the progression of chronic kidney disease, particularly with tubular atrophy. The fatty acid load on albumin significantly increases in obesity, presenting a proinflammatory environment to the proximal tubules. However, little is known about changes in the redox milieu during fatty acid overload and how redox-sensitive mechanisms mediate cell death. Here, we show that albumin with fatty acid impurities or conjugated with palmitate but not albumin itself compromised mitochondrial and cell viability, membrane potential and respiration. Fatty acid overload led to a redox imbalance which deactivated the antioxidant protein peroxiredoxin 2 and caused a peroxide-mediated apoptosis through the redox-sensitive pJNK/caspase-3 pathway. Transfection of tubular cells with peroxiredoxin 2 was protective and mitigated apoptosis. Mitochondrial fatty acid entry and ceramide synthesis modulators suggested that mitochondrial β oxidation but not ceramide synthesis may modulate lipotoxic effects on tubular cell survival. These results suggest that albumin overloaded with fatty acids but not albumin itself changes the redox environment in the tubules, inducing a peroxide-mediated redox-sensitive apoptosis. Thus, mitigating circulating fatty acid levels may be an important factor in both preserving redox balance and preventing tubular cell damage in proteinuric diseases.
Oxidative Stress and Disease Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA 70808. krisztian.stadler@pbrc.edu.
Christine
C
Ruggiero
Carrie M
CM
Elks
Claudia
C
Kruger
Ellen
E
Cleland
Kaity
K
Addison
Robert C
RC
Noland
Krisztian
K
Stadler
D000418:Albumins / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000473:pathology; D005227:Fatty Acids / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism; D051381:Rats; D012710:Serum Albumin, Bovine / Q000494:pharmacology
D000418:Albumins; D005227:Fatty Acids; D010168:Palmitates; D012710:Serum Albumin, Bovine; D054464:Peroxiredoxins
albuminuria; apoptosis; lipotoxicity; peroxiredoxin; tubular cell