Mitoprotection preserves the renal vasculature in porcine metabolic syndrome
Mitoprotection preserves the renal vasculature in porcine metabolic syndrome
复制标题
DOI：
10.1113/ep086988
复制
发表时间：
2018-07-01
影响因子：
2.7
通讯作者：
Lerman, Lilach O.
中科院分区：
文献类型：
--
作者：
Eirin, Alfonso;Hedayat, Ahmad F.;Lerman, Lilach O.
代谢综合征(METS)可导致肾内微血管疾病，可能与线粒体损伤有关。线粒体心磷脂靶向多肽elamipretide(ELAM)改善了狭窄后肾脏的微循环，但其减轻蛋氨酸诱导的肾血管损伤的能力尚不清楚。我们假设ELAM的慢性治疗会减少猪Met的肾血管重构和功能。研究了16周后的日粮诱导蛋氨酸，最后4周每天注射ELAM(0.1 mg kg(-1))的蛋氨酸，以及瘦肉对照(Lean)动物(n=6)。采用多层螺旋CT测量单肾区域血流灌注、血流量和肾小球滤过率。原位检测肾小管周围毛细血管(PTC)内皮细胞(EC)线粒体密度和心磷脂含量，以及PTC-EC的凋亡和氧化应激。观察PTCs(苏木精-伊红染色)、肾微血管空间密度(Micro-CT)和肾动脉内皮细胞功能(脏器槽)。与Lean相比，METS猪的肾血流和肾小球滤过率较高，但局部灌注量和血肌酐仍得到保护。线粒体密度和心磷脂含量在蛋氨酸PTC-ECs中降低，但在Elam处理的猪中改善，PTC密度也是如此。伊拉米普利还可减轻PTC-EC的氧化应激和细胞凋亡。此外，Elam还可改善肾微血管密度，减少微血管重构，恢复肾动脉段内皮细胞一氧化氮的表达和内皮依赖性的松弛。综上所述，甲硫氨酸诱导的线粒体改变可能导致猪肾脏PTC和微血管丢失，并可能损害肾动脉内皮功能。使用ELAM的丝裂原保护保留了肾血管的等级，强调了其改善蛋氨酸肾血管损伤的潜力。
The metabolic syndrome (MetS) induces intrarenal microvascular disease, which may involve mitochondrial injury. The mitochondrial cardiolipin-targeting peptide elamipretide (ELAM) improves the microcirculation in post-stenotic kidneys, but its ability to attenuate MetS-induced renal vascular damage is unknown. We hypothesized that chronic treatment with ELAM would decrease renal vascular remodelling and function in swine MetS. Pigs were studied after 16weeks of diet-induced MetS, MetS treated for the last 4weeks with daily injections of ELAM (0.1mg kg(-1)), and lean control (Lean) animals (n=6 each). Single-kidney regional perfusion, blood flow and glomerular filtration rate were measured with multi-detector computed tomography (CT). Peritubular capillary (PTC) endothelial cell (EC) mitochondrial density and cardiolipin content were assessed in situ, as were PTC-EC apoptosis and oxidative stress. The spatial density of PTCs (Haematoxylin and Eosin staining) and renal microvessels (micro-CT), and renal artery endothelial function (organ bath) were characterized. Regional perfusion and serum creatinine were preserved in MetS pigs, but renal blood flow and glomerular filtration rate were higher compared with Lean. Mitochondrial density and cardiolipin content were diminished in MetS PTC-ECs, but improved in ELAM-treated pigs, as did PTC density. Elamipretide also attenuated PTC-EC oxidative stress and apoptosis. Furthermore, ELAM improved renal microvascular density, decreased microvascular remodelling and restored endothelial nitric oxide expression and endothelium-dependent relaxation of renal artery segments. In conclusion, MetS-induced mitochondrial alterations might contribute to renal PTC and microvascular loss and might impair renal artery endothelial function in pigs. Mitoprotection with ELAM preserved a hierarchy of renal vessels, underscoring its potential to ameliorate renal vascular injury in MetS.