Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States of America.
PLoS One. 2013 Jul 3;8(7):e67474. doi: 10.1371/journal.pone.0067474. Print 2013.
Atherosclerotic renal artery stenosis (ARAS) raises blood pressure and can reduce kidney function. Revascularization of the stenotic renal artery alone does not restore renal medullary structure and function. This study tested the hypothesis that addition of mesenchymal stem cells (MSC) to percutaneous transluminal renal angioplasty (PTRA) can restore stenotic-kidney medullary tubular transport function and attenuate its remodeling. Twenty-seven swine were divided into three ARAS (high-cholesterol diet and renal artery stenosis) and a normal control group. Six weeks after ARAS induction, two groups were treated with PTRA alone or PTRA supplemented with adipose-tissue-derived MSC (10 × 10(6) cells intra-renal). Multi-detector computed tomography and blood-oxygenation-level-dependent (BOLD) MRI studies were performed 4 weeks later to assess kidney hemodynamics and function, and tissue collected a few days later for histology and micro-CT imaging. PTRA effectively decreased blood pressure, yet medullary vascular density remained low. Addition of MSC improved medullary vascularization in ARAS+PTRA+MSC and increased angiogenic signaling, including protein expression of vascular endothelial growth-factor, its receptor (FLK-1), and hypoxia-inducible factor-1α. ARAS+PTRA+MSC also showed attenuated inflammation, although oxidative-stress remained elevated. BOLD-MRI indicated that MSC normalized oxygen-dependent tubular response to furosemide (-4.3 ± 0.9, -0.1 ± 0.4, -1.6 ± 0.9 and -3.6 ± 1.0 s(-1) in Normal, ARAS, ARAS+PTRA and ARAS+PTRA+MSC, respectively, p<0.05), which correlated with a decrease in medullary tubular injury score (R(2) = 0.33, p = 0.02). Therefore, adjunctive MSC delivery in addition to PTRA reduces inflammation, fibrogenesis and vascular remodeling, and restores oxygen-dependent tubular function in the stenotic-kidney medulla, although additional interventions might be required to reduce oxidative-stress. This study supports development of cell-based strategies for renal protection in ARAS.
动脉粥样硬化性肾动脉狭窄（ARAS）会升高血压并降低肾功能。单纯对狭窄的肾动脉进行血运重建并不能恢复肾髓质结构和功能。本研究旨在验证这样一个假设，即经皮腔内肾血管成形术（PTRA）联合间充质干细胞（MSC）治疗可以恢复狭窄肾脏的髓质管状转运功能，并减轻其重塑。27 头猪被分为三组：ARAS（高胆固醇饮食+肾动脉狭窄）组和正常对照组。ARAS 诱导 6 周后，两组分别接受单纯 PTRA 或 PTRA 联合脂肪组织来源 MSC（10×106 细胞经肾内注射）治疗。4 周后，通过多排 CT 和血氧水平依赖（BOLD）MRI 研究评估肾脏的血流动力学和功能，随后几天收集组织进行组织学和微 CT 成像。PTRA 可有效降低血压，但髓质血管密度仍较低。在 ARAS+PTRA+MSC 组中，MSC 的添加改善了肾髓质血管化，并增加了血管生成信号，包括血管内皮生长因子、其受体（FLK-1）和缺氧诱导因子-1α的蛋白表达。ARAS+PTRA+MSC 组还表现出炎症减轻，尽管氧化应激仍处于较高水平。BOLD-MRI 表明，MSC 使氧依赖性呋塞米诱导的管状反应正常化（分别为-4.3±0.9、-0.1±0.4、-1.6±0.9 和-3.6±1.0 s-1，在正常、ARAS、ARAS+PTRA 和 ARAS+PTRA+MSC 组中，p<0.05），这与髓质管状损伤评分的降低相关（R2=0.33，p=0.02）。因此，在 PTRA 治疗的基础上加用 MSC 可减少炎症、纤维化和血管重塑，并恢复狭窄肾脏髓质的氧依赖性管状功能，尽管可能需要进一步的干预措施来减少氧化应激。本研究支持开发用于 ARAS 肾保护的基于细胞的策略。
