Endothelin-A receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia
Endothelin-A receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia
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DOI：
10.1681/asn.2006060635
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发表时间：
2006-12-01
影响因子：
13.6
通讯作者：
Lerman, Lilach O.
中科院分区：
文献类型：
--
作者：
Chade, Alejandro R.;Krier, James D.;Lerman, Lilach O.
高胆固醇血症(HC)可通过损害肾微血管(MV)的功能或结构而引发早期肾损伤。内皮素(ET)系统在HC中上调，并可通过调节MV张力、生长因子和重塑对肾脏微循环产生影响。推测ET-A拮抗剂可能通过改善肾功能、减轻肾内MV的损伤来保护HC肾。在实验性HC、HC和慢性补充ET A受体阻滞剂ABT-627(HC+ET-A，0.75 mg/kg/d)12周后，评估猪的单肾功能和对内皮依赖性攻击的血流动力学反应，并与正常对照组进行比较。然后，使用三维显微计算机断层成像技术在体外研究肾MV的结构，并探索肾组织中的生长因子和重塑途径。与正常组相比，HC组大鼠肾脏MV密度增加(77.68+/-5.1对62.9+/-4.8条/cm(2)，p=0.04)，但血管内皮功能减弱。慢性阻断ET-A可上调肾血管生长因子，进一步增加肾MV密度(139.9+/-8.4VS/cm(2)，与正常和HC相比p=0.001)，减少肾组织和MV重塑。此外，阻断ET-A可减少MV的迂回性，改善MV的内皮功能，提示新生血管的稳定和成熟。HC时肾脏MV结构和功能的调节部分由内源性ET系统介导。值得注意的是，阻断ET-A促进了HC肾MV的增殖和成熟，改善了肾MV的重构和功能。这项研究提示了ET-A阻滞剂的新的肾脏保护作用，并支持进一步探索针对HC和动脉粥样硬化中的ET途径的策略。
dHypercholesterolemia (HC) may trigger early renal injury, partly by impairing the function or the structure of renal microvessels (MV). The endothelin (ET) system is upregulated in HC and can have an impact on the renal microcirculation by regulating MV tone, growth factors, and remodeling. It was hypothesized that ET-A blockade would protect the HC kidney by improving the function and attenuating the damage of intrarenal MV. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 wk of experimental HC, HC and chronic supplementation with the ET receptor A blocker ABT-627 (HC+ET-A, 0.75 mg/kg per d), and normal controls. Renal MV architecture then was studied ex vivo using three-dimensional microcomputed tomography imaging, and growth factors and remodeling pathways were explored in renal tissue. The HC kidney showed increased MV density compared with normal (77.68 +/- 5.1 versus 62.9 +/- 4.8 vessels/cm(2); p = 0.04) but blunted endothelial function. Chronic ET-A blockade in HC upregulated renal vascular growth factors, further increased renal MV density (139.9 +/- 8.4 vessels/cm(2); p = 0.001 versus normal and HC), and decreased renal tissue and MV remodeling. Furthermore, ET-A blockade in HC decreased MV tortuosity and improved MV endothelial function, suggesting accelerated stabilization and maturation of neo-vessels. Modulation of renal MV architecture and function in HC is mediated partly by the endogenous ET system. Notably, ET-A blockade enhanced the proliferation and facilitated the maturation of renal MV in the HC kidney and improved renal MV remodeling and function. This study suggests novel renoprotective effects of ET-A blockers and supports further exploration of strategies that target the ET pathway in HC and atherosclerosis.