Eirin Alfonso, Ebrahimi Behzad, Zhang Xin, Zhu Xiang-Yang, Woollard John R, He Quan, Textor Stephen C, Lerman Amir, Lerman Lilach O
Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, FL, USA.
Cardiovasc Res. 2014 Sep 1;103(4):461-72. doi: 10.1093/cvr/cvu157. Epub 2014 Jun 19.
The mechanisms responsible for renal injury in atherosclerotic renovascular disease (ARVD) are incompletely understood, and few therapeutic options are available to reverse it. We hypothesized that chronic renal damage involves mitochondrial injury, and that mitochondrial protection would reduce renal fibrosis and dysfunction in ARVD pigs.
Domestic pigs were studied after 10 weeks of ARVD or sham, treated for the last 4 weeks with daily subcutaneous injections (5 days/week) of vehicle or Bendavia (0.1 mg/kg), a tetrapeptide that preserves cardiolipin content in the mitochondrial inner membrane. Single-kidney haemodynamics and function were studied using fast-computer tomography, oxygenation using blood oxygen level-dependent magnetic resonance imaging, microvascular architecture, oxidative stress, and fibrosis ex vivo. Cardiolipin content was assessed using mass spectrometry and staining. Renal endothelial function was studied in vivo and ex vivo. In addition, swine renal artery endothelial cells incubated with tert-butyl hydroperoxide were also treated with Bendavia. Stenotic-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) decreased in ARVD + Vehicle compared with normal (318.8 ± 61.0 vs. 553.8 ± 82.8 mL/min and 48.0 ± 4.0 vs. 84.0 ± 3.8 mL/min, respectively) associated with loss of cardiolipin, intra-renal microvascular rarefaction, and hypoxia. Bendavia restored cardiolipin content in ARVD and improved vascular density, oxygenation, RBF (535.1 ± 24.9 mL/min), and GFR (86.6 ± 11.2 mL/min). Oxidative stress and fibrosis were ameliorated, and renovascular endothelial function normalized both in vivo and in vitro.
Preservation of mitochondrial cardiolipin attenuated swine stenotic-kidney microvascular loss and injury, and improved renal oxygenation, haemodynamics, and function. These observations implicate mitochondrial damage in renal deterioration in chronic experimental ARVD, and position the mitochondria as a central therapeutic target.
动脉粥样硬化性肾血管疾病（ARVD）中肾损伤的发病机制尚未完全明确，且几乎没有可逆转该疾病的治疗方法。我们推测慢性肾损伤涉及线粒体损伤，并且线粒体保护可减轻ARVD猪的肾纤维化和功能障碍。
对经过10周ARVD或假手术处理的家猪进行研究，在最后4周每天皮下注射（每周5天）溶媒或Bendavia（一种能维持线粒体内膜心磷脂含量的四肽，剂量为0.1mg/kg）。使用快速计算机断层扫描研究单肾血流动力学和功能，利用血氧水平依赖磁共振成像研究氧合情况，对微血管结构、氧化应激和纤维化进行离体研究。通过质谱分析和染色评估心磷脂含量，并在体内和体外研究肾内皮功能。此外，用叔丁基过氧化氢孵育的猪肾动脉内皮细胞也用Bendavia进行处理。与正常情况相比，ARVD + 溶媒组狭窄肾的肾血流量（RBF）和肾小球滤过率（GFR）降低（分别为318.8±61.0 vs. 553.8±82.8 mL/min和48.0±4.0 vs. 84.0±3.8 mL/min），同时伴有心磷脂丢失、肾内微血管稀疏和缺氧情况发生。Bendavia可恢复ARVD猪的心磷脂含量，并改善血管密度、氧合、RBF（535.1±24.9 mL/min）和GFR（86.6±11.2 mL/min）。氧化应激和纤维化得到改善，肾血管内皮功能在体内和体外均恢复正常。
维持线粒体心磷脂可减轻猪狭窄肾的微血管丢失和损伤，并改善肾氧合、血流动力学及功能状况。这些观察结果表明线粒体损伤参与了慢性实验性ARVD的肾恶化过程，并将线粒体定位为主要治疗靶点。
