前列地尔减轻大鼠肾缺血再灌注损伤中的线粒体损伤。
Treprostinil reduces mitochondrial injury during rat renal ischemia-reperfusion injury.
机构信息
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Road, Kingston, RI 0288, USA.
Division of Renal Disease, Department of Medicine, Rhode Island Hospital, Warren Alpert School of Medicine Brown University, 222 Richmond Street, Providence, RI 02903, USA.
出版信息
Biomed Pharmacother. 2021 Sep;141:111912. doi: 10.1016/j.biopha.2021.111912. Epub 2021 Jul 15.
BACKGROUND
Renal ischemia-reperfusion injury (IRI) is a major factor contributing to acute kidney injury and it is associated with a high morbidity and mortality if untreated. Renal IRI depletes cellular and tissue adenosine triphosphate (ATP), which compromises mitochondrial function, further exacerbating renal tubular injury. Currently, no treatment for IRI is available. This study investigates the protective role of treprostinil in improving mitochondria biogenesis and recovery during rat renal IRI.
METHODS
Male Sprague Dawley rats were randomly assigned to groups: control, sham, IRI-placebo or IRI-treprostinil and subjected to 45 min of bilateral renal ischemia followed by 1-72 h reperfusion. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump.
RESULTS
Treprostinil significantly reduced peak elevated serum creatinine (SCr) levels and accelerated normalization relative to IRI-placebo (p < 0.0001). Treatment with treprostinil also inhibited IRI-mediated renal apoptosis, mitochondrial oxidative injury (p < 0.05), and the release of cytochrome c (p < 0.01) vs. IRI-placebo. In addition, treprostinil preserved renal mitochondrial DNA copy number (p < 0.0001) and renal ATP levels (p < 0.05) to nearly those of sham-operated animals. Non-targeted semi-quantitative proteomics showed reduced levels of ATP synthase subunits in the IRI-placebo group which were restored to sham levels by treprostinil treatment (p < 0.05). Furthermore, treprostinil reduced renal IRI-induced upregulated Drp1 and pErk protein levels, and restored Sirt3 and Pgc-1α levels to baseline (p < 0.05).
CONCLUSIONS
Treprostinil reduces mitochondrial-mediated renal apoptosis, inhibits mitochondria fission, and promotes mitochondria fusion, thereby accelerating mitochondrial recovery and protecting renal proximal tubules from renal IRI. These results support the clinical investigation of treprostinil as a viable therapy to reduce renal IRI.
背景
肾缺血再灌注损伤（IRI）是导致急性肾损伤的主要因素，如果不治疗，其发病率和死亡率很高。肾 IRI 会耗尽细胞和组织三磷酸腺苷（ATP），从而损害线粒体功能，进一步加重肾小管损伤。目前，尚无针对 IRI 的治疗方法。本研究探讨了曲前列尼尔在改善大鼠肾 IRI 期间线粒体生物发生和恢复中的保护作用。
方法
雄性 Sprague Dawley 大鼠随机分为对照组、假手术组、IRI-安慰剂组或 IRI-曲前列尼尔组，并进行 45 分钟的双侧肾缺血，然后再灌注 1-72 小时。通过皮下渗透微型泵给予安慰剂或曲前列尼尔（100ng/kg/min）。
结果
与 IRI-安慰剂组相比，曲前列尼尔显著降低了峰值升高的血清肌酐（SCr）水平，并加速了其正常化（p<0.0001）。与 IRI-安慰剂组相比，曲前列尼尔还抑制了 IRI 介导的肾细胞凋亡、线粒体氧化损伤（p<0.05）和细胞色素 c 的释放（p<0.01）。此外，曲前列尼尔还保持了肾线粒体 DNA 拷贝数（p<0.0001）和肾 ATP 水平（p<0.05）接近假手术组动物的水平。非靶向半定量蛋白质组学显示，IRI-安慰剂组中 ATP 合酶亚基水平降低，而曲前列尼尔治疗可将其恢复至假手术组水平（p<0.05）。此外，曲前列尼尔降低了肾 IRI 诱导的上调的 Drp1 和 pErk 蛋白水平，并将 Sirt3 和 Pgc-1α 水平恢复至基线（p<0.05）。
结论
曲前列尼尔减少了线粒体介导的肾细胞凋亡，抑制了线粒体分裂，并促进了线粒体融合，从而加速了线粒体的恢复，保护了肾近端小管免受肾 IRI 的损伤。这些结果支持将曲前列尼尔作为一种可行的治疗方法来减少肾 IRI 的临床研究。
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