SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells |
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Authors: | Koyama Tetsuro Kume Shinji Koya Daisuke Araki Shin-ichi Isshiki Keiji Chin-Kanasaki Masami Sugimoto Toshiro Haneda Masakazu Sugaya Takeshi Kashiwagi Atsunori Maegawa Hiroshi Uzu Takashi |
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Affiliation: | a Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japanb Division of Endocrinology and Metabolism, Kanazawa Medical University, Kahoku-Gun, Ishikawa, Japanc Second Department of Medicine, Asahikawa Medical College, Asahikawa, Hokkaido, Japand Nephrology and Hypertension, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan |
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Abstract: | Free fatty acid (FFA)-mediated renal lipotoxicity is associated with the progression of tubulointerstitial inflammation in proteinuric kidney disease. SIRT3 is an antiaging molecule regulated by calorie restriction and mitochondria-localized NAD+-dependent deacetylase. In this study, we investigated whether SIRT3 reversed renal lipotoxicity-mediated ROS and inflammation. In the kidney of the FFA-bound BSA-overloaded mouse, which is a well-established experimental model of FFA-associated tubulointerstitial inflammation, mRNA expression of SIRT3 was significantly decreased and negatively correlated with mRNA expression of an inflammatory cytokine, monocyte chemoattractant protein-1 (MCP-1). In cultured proximal tubular (mProx) cells, the saturated FFA palmitate stimulated ROS accumulation and expression of MCP-1. These effects were ameliorated by retrovirus-mediated overexpression of SIRT3, whereas they were exacerbated by either overexpression of a dominant-negative form of SIRT3(N87A) lacking deacetylase activity or knockdown of SIRT3 by siRNA transfection. Furthermore, we showed that SIRT3 positively regulated both mitochondrial oxidative capacity and antioxidant gene expression, thereby reducing ROS accumulation in mProx cells, which suggests a mechanism that underlies SIRT3-mediated reversal of palmitate-induced inflammation. In conclusion, these results highlight a new role for SIRT3 in lipotoxicity/ROS-related inflammation, reveal a new molecular mechanism underlying calorie restriction-mediated antioxidant and anti-inflammatory effects, and could aid in the design of new therapies for the prevention of tubulointerstitial lesions in proteinuric kidney disease. |
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Keywords: | CR, calorie restriction FFA, free fatty acid 4-HNE, 4-hydroxy-2-nonenal MnSOD, manganese superoxide dismutase MAPK, mitogen-activated protein kinase MCP-1, monocyte chemoattractant protein-1 OCR, oxygen consumption rate ROS, reactive oxygen species TNF-α, tumor necrosis factor-α |
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