Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis
Mechanisms of renal structural alterations in combined hypercholesterolemia and renal artery stenosis
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DOI：
10.1161/01.atv.0000077477.40824.52
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发表时间：
2003-07-01
影响因子：
8.7
通讯作者：
Lerman, LO
中科院分区：
文献类型：
--
作者：
Chade, AR;Rodriguez-Porcel, M;Lerman, LO
目的 - 动脉粥样硬化性肾血管疾病（ARVD）比其他肾动脉狭窄（RAS）病因更易加重肾瘢痕形成，但这种潜在促纤维化作用的潜在致病机制仍不清楚。我们验证了动脉粥样硬化与RAS共存会干扰肾组织重塑这一假设。
方法与结果 - 采用电子束计算机断层扫描在体内对3组猪（每组n = 7）的单肾血流动力学和功能进行量化：正常猪、诱导单侧RAS 12周后的猪（RAS组）以及喂食12周2%高胆固醇饮食且具有相似程度RAS的猪（HC + RAS，模拟早期ARVD）。通过蛋白质印迹法和免疫组织化学对肾脏进行体外研究。RAS和HC + RAS缺血肾脏的肾体积、肾血流量和肾小球滤过率均有相似程度的降低，同时伴有转化生长因子 - β、金属蛋白酶组织抑制剂 - 1和纤溶酶原激活物抑制剂 - 1等促纤维化因子表达的相似增加。然而，与仅患RAS的肾脏相比，HC + RAS肾脏显示肾内纤维化增加。此外，核因子 - κB表达增加，细胞外（基质金属蛋白酶 - 2）和细胞内（泛素）蛋白质降解系统表达降低，细胞凋亡减弱。
结论 - 在RAS基础上叠加饮食诱导的高胆固醇血症通过放大促纤维化机制和破坏组织重塑，加速狭窄肾脏纤维化的发展。这些改变可能导致ARVD中肾脏疾病的进展，并可能解释终末期肾病倾向增加的原因。
Objective-Atherosclerotic renovascular disease (ARVD) aggravates renal scarring more than other causes of renal artery stenosis (RAS), but the underlying pathogenic mechanisms of this potential profibrotic effect remain unclear. We tested the hypothesis that coexistence of atherosclerosis and RAS interferes with renal tissue remodeling.Methods and Results-Single-kidney hemodynamics and function were quantified in vivo with electron-beam computed tomography in 3 groups of pigs (n=7 each): normal pigs, pigs 12 weeks after induction of unilateral RAS (RAS group), and pigs with similar-degree RAS fed a 12-week 2% hypercholesterolemic diet (HC+RAS, simulating early ARVD). Kidneys were studied ex vivo by Western blotting and immunohistochemistry. Renal volume, renal blood flow, and glomerular filtration rate were similarly decreased in RAS and HC+RAS ischemic kidneys, accompanied by similar increased expression of profibrotic factors like transforming growth factor-beta, tissue inhibitor of metalloproteinase-1, and plasminogen activator inhibitor-1. Nevertheless, HC+RAS kidneys showed increased intrarenal fibrosis compared with RAS-only kidneys. Furthermore, expression of nuclear factor-kappaB was increased, expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems was decreased, and apoptosis was blunted.Conclusions-Diet-induced HC superimposed on RAS accelerates the development of fibrosis in the stenotic kidney by amplifying profibrotic mechanisms and disrupting tissue remodeling. These alterations might contribute to renal disease progression in ARVD and might account for the increased propensity for end-stage renal disease.