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.
['Ruggiero|Christine|C|', 'Elks|Carrie M|CM|', 'Kruger|Claudia|C|', 'Cleland|Ellen|E|', 'Addison|Kaity|K|', 'Noland|Robert C|RC|', 'Stadler|Krisztian|K|']
D000418:Albumins D000818:Animals D017209:Apoptosis D002470:Cell Survival D002478:Cells, Cultured D004847:Epithelial Cells D005227:Fatty Acids D007687:Kidney Tubules, Proximal D053078:Membrane Potential, Mitochondrial D008928:Mitochondria D010084:Oxidation-Reduction D010168:Palmitates D054464:Peroxiredoxins D051381:Rats D012710:Serum Albumin, Bovine
apoptosis albuminuria peroxiredoxin tubular cell lipotoxicity