1 The Elmezzi Graduate School of Molecular Medicine, Manhasset, NY. 2 Department of Surgery, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY. 3 Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY. 4 Department of Pathology, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY. 5 Address correspondence to: Ping Wang, M.D., Center for Translational Research, Feinstein Institute for Medical Research, 350 Community Dr., Manhasset, NY 11030.
Transplantation. 2014 Jul 27;98(2):148-56. doi: 10.1097/TP.0000000000000194.
Renal ischemia-reperfusion (I/R) is a major contributor to delayed graft function after renal transplantation. The pathophysiology of I/R can be summarized by a primary energy deficit during ischemia and a secondary phase of oxidative stress and inflammation. Sirtuin 1 is an energy-sensing enzyme involved in regulating multiple cellular functions. We hypothesized that stimulating Sirtuin 1 would increase mitochondrial biogenesis thereby enhancing energy metabolism and attenuating I/R-induced renal injury.
Adult male rats were subjected to 60 min of bilateral renal pedicle clamping. SRT1720 (5 mg/kg body weight) or vehicle (20% dimethyl sulfoxide in saline) was administered intravenously at reperfusion. Blood and renal tissues were collected 24 hr after reperfusion.
Posttreatment with SRT1720 significantly improved renal histologic architecture, decreased apoptosis, and reduced serum aspartate aminotransferase and creatinine levels compared to the vehicle. Renal adenosine triphosphate (ATP) levels were reduced by 48% after I/R, whereas SRT1720 restored ATP to 77% of control. Further, SRT1720 reversed the loss of renal mitochondrial mass induced by I/R supported by an increased expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and its downstream mediators. SRT1720 also increased ATP levels and mitochondrial mass in human renal HK-2 cells. Moreover, SRT1720 decreased the levels of malondialdehyde, nitrotyrosine, and inducible nitric oxide synthase expression compared to the vehicle. A marked decrease in macrophage infiltration by SRT1720 treatment was associated with a decrease in tumor necrosis factor-α expression and a decrease in IκB-α degradation and nuclear factor-κB phosphorylation after I/R.
SRT1720 treatment enhanced energy metabolism by stimulating mitochondrial biogenesis as well as decreasing nitrosative stress and inflammation, thereby attenuating I/R-induced renal injury.
肾缺血再灌注（I/R）是肾移植后延迟移植物功能的主要原因。I/R 的病理生理学可以概括为缺血期间的原发性能量不足和继发性氧化应激和炎症阶段。Sirtuin 1 是一种参与调节多种细胞功能的能量感应酶。我们假设刺激 Sirtuin 1 会增加线粒体生物发生，从而增强能量代谢并减轻 I/R 引起的肾损伤。
成年雄性大鼠接受 60 分钟的双侧肾蒂夹闭。在再灌注时静脉内给予 SRT1720（5mg/kg 体重）或载体（20%二甲亚砜在盐水中）。再灌注后 24 小时收集血液和肾组织。
与载体相比，SRT1720 治疗后可显著改善肾组织学结构，减少细胞凋亡，并降低血清天冬氨酸转氨酶和肌酐水平。I/R 后肾腺苷三磷酸（ATP）水平降低 48%，而 SRT1720 将 ATP 恢复至对照的 77%。此外，SRT1720 逆转了 I/R 引起的肾线粒体质量丧失，其支持物是过氧化物酶体增殖物激活受体γ共激活因子 1-α及其下游介质的表达增加。SRT1720 还增加了人肾 HK-2 细胞中的 ATP 水平和线粒体质量。此外，与载体相比，SRT1720 降低了丙二醛、硝基酪氨酸和诱导型一氧化氮合酶的水平。SRT1720 治疗后巨噬细胞浸润明显减少，与肿瘤坏死因子-α表达减少以及 IκB-α 降解和核因子-κB 磷酸化减少有关。
SRT1720 通过刺激线粒体生物发生以及减少硝化应激和炎症来增强能量代谢，从而减轻 I/R 引起的肾损伤。
