SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells
SIRT3 attenuates palmitate-induced ROS production and inflammation in proximal tubular cells
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DOI：
10.1016/j.freeradbiomed.2011.05.028
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发表时间：
2011-09-15
影响因子：
7.4
通讯作者：
Uzu, Takashi
中科院分区：
文献类型：
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作者：
Koyama, Tetsuro;Kume, Shinji;Uzu, Takashi
游离脂肪酸（FFA）介导的肾脂毒性与蛋白尿肾病肾小管间质炎症的进展相关。SIRT3是一种抗衰老分子，受热量限制和NAD（+）依赖性脱乙酰酶的调节。在这项研究中，我们研究了SIRT3是否逆转肾脂毒性介导的ROS和炎症。在FFA结合的BSA超载小鼠的肾脏中，这是FFA相关的肾小管间质炎症的良好建立的实验模型，SIRT3的mRNA表达显著降低，并且与炎性细胞因子单核细胞趋化蛋白-1（MCP-1）的mRNA表达呈负相关。在培养的近端肾小管（mProx）细胞中，饱和FFA棕榈酸刺激ROS积累和MCP-1的表达。逆转录病毒介导的SIRT3过表达改善了这些效应，而缺乏脱乙酰酶活性的SIRT3（N87A）的显性负性形式的过表达或siRNA转染的SIRT3敲低则加剧了这些效应。此外，我们发现SIRT 3正调节线粒体氧化能力和抗氧化基因表达，从而减少mProx细胞中的活性氧积累，这表明SIRT 3介导逆转棕榈酸诱导炎症的机制。总之，这些结果突出了SIRT3在脂毒性/ROS相关炎症中的新作用，揭示了卡路里限制介导的抗氧化和抗炎作用的新分子机制，并有助于设计新的治疗方法，以预防蛋白尿肾病中的肾小管间质病变。(C)2011 Elsevier Inc. All rights reserved.
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. (C) 2011 Elsevier Inc. All rights reserved.