Pathways of renal fibrosis and modulation of matrix turnover in experimental hypercholesterolemia
Pathways of renal fibrosis and modulation of matrix turnover in experimental hypercholesterolemia
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DOI：
10.1161/01.hyp.0000184250.37607.da
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发表时间：
2005-10-01
期刊：
影响因子：
8.3
通讯作者：
Lerman, LO
中科院分区：
文献类型：
--
作者：
Chade, AR;Mushin, OP;Lerman, LO
血脂异常常常伴随并加速肾脏疾病，部分是通过促进纤维化。然而，介导这种作用的机制尚不清楚。我们假设高胆固醇血症调节几种相互关联的通路，这些通路促进细胞外基质的沉积并减弱其降解，并且通过逆转高胆固醇血症可以对这些通路进行调控。14头猪接受为期16周含2%高胆固醇的饮食（高胆固醇 - 高胆固醇组；n = 7）或正常饮食（n = 7），而另外7头猪先接受10周高胆固醇饮食，接着接受6周正常饮食（高胆固醇 - 正常组）。通过电子束计算机断层扫描在体内评估肾内皮功能，然后使用蛋白质印迹法、实时定量聚合酶链反应、明胶酶谱法和免疫染色在体外研究肾组织。高胆固醇 - 高胆固醇组的肾脏显示内皮功能障碍，伴有肾内氧化应激增加、炎症、内皮素和转化生长因子 - β系统的激活，以及基质金属蛋白酶表达和活性降低。相应地，高胆固醇 - 高胆固醇组的肾脏显示Ⅳ型胶原蛋白表达增加和纤维化。降脂饮食干预逆转了大多数这些变化。总之，这项研究表明，早期动脉粥样硬化中的肾纤维化是细胞外基质沉积同时增加以及基质金属蛋白酶介导的降解减弱的结果，总体上促进了血管周围和肾小管间质纤维化。值得注意的是，在高胆固醇血症中，这些通路中的许多可能是可逆的，并且有可能确定关键靶点用于早期干预以保护肾脏。
Dyslipidemia often accompanies and accelerates renal disease, partly by promoting fibrosis. However, the mechanisms mediating this effect are unclear. We hypothesized that hypercholesterolemia modulates several interlinked pathways that promote deposition and blunt degradation of extracellular matrix, and that these could be manipulated by reversal of hypercholesterolemia. Fourteen pigs were fed a 16-week 2% high-cholesterol diet (HC-HC; n=7) or normal diet (n=7), whereas in 7 others, a 10-week HC was followed by a 6-week normal diet (HC-N). Renal endothelial function was assessed in vivo with electron-beam computed tomography, and renal tissue was then studied ex vivo using Western blot, real-time quantitative polymerase chain reaction, gelatin zymography, and immunostaining. HC-HC kidneys showed endothelial dysfunction, accompanied by increased intrarenal oxidative stress, inflammation, activation of the endothelin and transforming-growth factor-beta systems, and decreased matrix metalloproteinase expression and activity. Accordingly, HC-HC kidneys showed increased collagen IV expression and fibrosis. A lipid-lowering dietary intervention reversed most of these changes. In conclusion, this study indicates that renal fibrosis in early atherosclerosis is a result of a simultaneous increase in extracellular matrix deposition and blunted matrix metalloproteinase-mediated degradation, overall promoting perivascular and tubulointerstitial fibrosis. Notably, many of these pathways may be reversible in hypercholesterolemia, and crucial targets could potentially be identified for early interventions to preserve the kidney.