Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury
Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury
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DOI：
10.1124/jpet.114.214700
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发表时间：
2014-08-01
影响因子：
3.5
通讯作者：
Schnellmann, Rick G.
中科院分区：
文献类型：
--
作者：
Garrett, Sara M.;Whitaker, Ryan M.;Schnellmann, Rick G.
许多急性和慢性病症，如急性肾损伤、慢性肾病、心力衰竭和肝病，涉及线粒体功能障碍。虽然我们已经提供了证据表明，药物诱导的线粒体生物合成（MB）的刺激加速线粒体和细胞修复，导致器官功能的恢复，只有有限数量的化学物质已被确定，诱导MB。本研究的目的是评估5-羟色胺1F（5-HT 1F）受体在MB中的作用。免疫印迹和定量聚合酶链反应分析显示，5-HT 1F受体在肾近端小管细胞（RPTC）的表达。MB筛选试验表明，两种选择性5-HT 1F受体激动剂LY 334370（4-氟-N-[3-（1-甲基-4-哌啶基）-1H-吲哚-5-基]苯甲酰胺）和LY 344864（N-[（3R）-3-（二甲基氨基）-2，3，4，9-四氢-1H-咔唑-6-基]-4-氟苯甲酰胺; 1-100 nM）增加了RPTC中羰腈-对三氟甲氧基苯腙-解偶联的耗氧量，并且验证研究证实了两种激动剂都增加了线粒体蛋白[例如，ATP合酶β、细胞色素c氧化酶1（Cox 1）和NADH脱氢酶（泛醌）1 β亚复合物亚基8（NDUFB 8）]。小干扰RNA敲低5-HT 1F受体阻断激动剂诱导的MB。此外，LY 344864增加了小鼠肾皮质、心脏和肝脏中过氧化物酶体增殖物激活受体辅激活因子1-α、Cox 1和NDUFB 8的转录水平和线粒体DNA（mtDNA）拷贝数。最后，LY 344864加速了肾功能的恢复，如缺血/再灌注诱导的急性肾损伤（阿基）后血尿素氮和肾损伤分子1降低以及mtDNA拷贝数增加所示。总之，这些研究揭示了5-HT 1F受体与MB相关，5-HT 1F受体激动在体外和体内促进MB，并且5-HT 1F受体激动促进从阿基损伤中恢复。通过5-HT 1F受体激动诱导MB代表了治疗线粒体器官功能障碍的新靶点和方法。
Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB. The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists, LY334370 (4-fluoro-N-[3-(1-methyl- 4-piperidinyl)-1H-indol-5-yl] benzamide) and LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]- 4-fluorobenzamide; 1-100 nM) increased carbonylcyanide-p-trifluoromethoxyphenylhydrazone-uncoupled oxygen consumption in RPTC, and validation studies confirmed both agonists increased mitochondrial proteins [e.g., ATP synthase beta, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8 (NDUFB8)] in vitro. Small interfering RNA knockdown of the 5-HT1F receptor blocked agonist-induced MB. Furthermore, LY344864 increased peroxisome proliferator-activated receptor coactivator 1-alpha, Cox1, and NDUFB8 transcript levels and mitochondrial DNA (mtDNA) copy number in murine renal cortex, heart, and liver. Finally, LY344864 accelerated recovery of renal function, as indicated by decreased blood urea nitrogen and kidney injury molecule 1 and increased mtDNA copy number following ischemia/reperfusion-induced acute kidney injury (AKI). In summary, these studies reveal that the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and 5-HT1F receptor agonism promotes recovery from AKI injury. Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction.