A Mitochondrial Permeability Transition Pore Inhibitor Improves Renal Outcomes After Revascularization in Experimental Atherosclerotic Renal Artery Stenosis
A Mitochondrial Permeability Transition Pore Inhibitor Improves Renal Outcomes After Revascularization in Experimental Atherosclerotic Renal Artery Stenosis
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DOI：
10.1161/hypertensionaha.112.199919
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发表时间：
2012-11-01
期刊：
影响因子：
8.3
通讯作者：
Lerman, Lilach O.
中科院分区：
文献类型：
--
作者：
Eirin, Alfonso;Li, Zilun;Lerman, Lilach O.
动脉粥样硬化性肾动脉狭窄（ARAS）患者，血运重建可改善血压，但不能改善肾功能，这可能与肾再灌注损伤有关。Bendavia是一种抑制线粒体通透性转换孔开放的新型四肽，可减少实验模型中的细胞凋亡、氧化应激和缺血-再灌注损伤。然而，其改善慢性ARAS血运重建肾反应的潜力尚不清楚。我们假设，辅助Bendavia将改善经皮腔内肾血管成形术（PTRA）后的肾脏结构和功能。在6周ARAS或对照后，对猪进行PTRA+支架植入（或假手术）治疗，在PTRA期间辅助连续4小时输注Bendavia（0.05 mg/kg IV）或溶剂（各n=7）。4周后研究单肾肾血流量和肾小球滤过率，并离体评价肾线粒体生物发生、微血管结构和损伤途径。PTRA后单核细胞趋化蛋白-1水平升高，提示炎症损伤。Bendavia没有立即影响炎性细胞因子水平，但4周后，与ARAS+PTRA+溶媒相比，ARAS+PTRA+Bendavia组狭窄肾肾血流量和肾小球滤过率均改善（分别为44.00 +/- 0.21%和36.40 +/-10.21%）。PTRA+Bendavia治疗后，肾线粒体生物合成恢复，微血管稀疏、细胞凋亡、氧化应激、肾小管损伤和纤维化减少。在猪ARAS中，PTRA期间输注Bendavia可保护线粒体生物发生、肾血流动力学和功能，并减轻组织损伤。因此，肾再灌注过程中功能性线粒体损伤可能维持肾炎症损伤并限制PTRA后的肾恢复。有效的抗凋亡和抗氧化作用为Bendavia提供了一种新的治疗潜力，用于改善实验性ARAS中PTRA后的肾脏结局。（高血压。2012;60：1242-1249.）。在线补充资料
Revascularization improves blood pressure but not renal function in most patients with atherosclerotic renal artery stenosis (ARAS), possibly related to injury incurred during renal reperfusion. Bendavia, a novel tetrapeptide that inhibits mitochondrial permeability transition pore opening, reduces apoptosis, oxidative stress, and ischemia-reperfusion injury in experimental models. However, its potential for improving renal response to revascularization of chronic ARAS is unknown. We hypothesized that adjunct Bendavia would improve renal structure and function after percutaneous transluminal renal angioplasty (PTRA). Pigs were treated after 6 weeks of ARAS or control with PTRA+stenting (or sham), adjunct continuous 4-hour infusion of Bendavia (0.05 mg/kg IV) or vehicle (n=7 each) during PTRA. Single-kidney renal blood flow and glomerular filtration rate were studied 4 weeks later and renal mitochondrial biogenesis, microvascular architecture, and injurious pathways evaluated ex vivo. Monocyte chemoattractant protein-1 levels rose after PTRA, suggesting inflammatory injury. Bendavia did not immediately affect inflammatory cytokine levels, yet 4 weeks later, stenotic kidney renal blood flow and glomerular filtration rate both improved (44.00 +/- 0.21% and 36.40 +/- 10.21%, respectively) in ARAS+PTRA+Bendavia compared with ARAS+PTRA+vehicle. Renal mitochondrial biogenesis was restored after PTRA+Bendavia, and microvascular rarefaction, apoptosis, oxidative stress, tubular injury, and fibrosis decreased. Infusion of Bendavia during PTRA preserved mitochondrial biogenesis, renal hemodynamics, and function, and attenuated tissue injury in swine ARAS. Thus, functional mitochondrial injury during renal reperfusion may sustain renal inflammatory injury and limit kidney recovery after PTRA. Potent antiapoptotic and antioxidant effects provide Bendavia a novel therapeutic potential for improving kidney outcomes after PTRA in experimental ARAS. (Hypertension. 2012;60:1242-1249.). Online Data Supplement