Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
Free Radic Biol Med. 2011 Sep 15;51(6):1258-67. doi: 10.1016/j.freeradbiomed.2011.05.028. Epub 2011 May 30.
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.
游离脂肪酸（FFA）介导的肾脂毒性与蛋白尿肾病中肾小管间质炎症的进展有关。SIRT3 是一种抗衰老分子，受热量限制和线粒体定位的 NAD（+）依赖性脱乙酰酶调节。在这项研究中，我们研究了 SIRT3 是否逆转了肾脂毒性介导的 ROS 和炎症。在 FFA 结合 BSA 过载的小鼠肾脏中，SIRT3 的 mRNA 表达显著降低，与炎症细胞因子单核细胞趋化蛋白-1（MCP-1）的 mRNA 表达呈负相关，这是一种公认的 FFA 相关肾小管间质炎症的实验模型。在培养的近端肾小管（mProx）细胞中，饱和脂肪酸棕榈酸刺激 ROS 积累和 MCP-1 的表达。SIRT3 的逆转录病毒介导过表达减轻了这些作用，而 SIRT3 缺乏脱乙酰酶活性的显性负形式（N87A）的过表达或 siRNA 转染对 SIRT3 的敲低则加剧了这些作用。此外，我们表明 SIRT3 可正向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 ROS 的积累，这表明了 SIRT3 介导的逆转棕榈酸诱导的炎症的潜在机制。总之，这些结果突出了 SIRT3 在脂毒性/ROS 相关炎症中的新作用，揭示了热量限制介导的抗氧化和抗炎作用的新分子机制，并可能有助于设计预防蛋白尿肾病中肾小管间质损伤的新疗法。
