Wang Cheng, Luo Zaiming, Kohan Donald, Wellstein Anton, Jose Pedro A, Welch William J, Wilcox Christopher S, Wang Dan
From the Hypertension, Kidney and Vascular Research Center and Division of Nephrology and Hypertension, Department of Medicine (C.W., Z.L., W.J.W., C.S.W., D.W.) and Department of Oncology, Lombardi Cancer Center (A.W.), Georgetown University, Washington, DC; Department of Nephrology, The Third Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China (C.W.); Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City (D.K.); and Division of Nephrology, Department of Medicine and Department of Physiology, University of Maryland, Baltimore, MD (P.A.J.).
Hypertension. 2015 May;65(5):1055-63. doi: 10.1161/HYPERTENSIONAHA.115.05244. Epub 2015 Mar 2.
Cardiovascular disease is frequent in chronic kidney disease and has been related to angiotensin II, endothelin-1 (ET-1), thromboxane A2, and reactive oxygen species (ROS). Because activation of thromboxane prostanoid receptors (TP-Rs) can generate ROS, which can generate ET-1, we tested the hypothesis that chronic kidney disease induces cyclooxygenase-2 whose products activate TP-Rs to enhance ET-1 and ROS generation and contractions. Mesenteric resistance arterioles were isolated from C57/BL6 or TP-R+/+ and TP-R-/- mice 3 months after SHAM-operation (SHAM) or surgical reduced renal mass (RRM, n=6/group). Microvascular contractions were studied on a wire myograph. Cellular (ethidium: dihydroethidium) and mitochondrial (mitoSOX) ROS were measured by fluorescence microscopy. Mice with RRM had increased excretion of markers of oxidative stress, thromboxane, and microalbumin; increased plasma ET-1; and increased microvascular expression of p22(phox), cyclooxygenase-2, TP-Rs, preproendothelin and endothelin-A receptors, and increased arteriolar remodeling. They had increased contractions to U-46,619 (118 ± 3 versus 87 ± 6, P<0.05) and ET-1 (108 ± 5 versus 89 ± 4, P<0.05), which were dependent on cellular and mitochondrial ROS, cyclooxygenase-2, and TP-Rs. RRM doubled the ET-1-induced cellular and mitochondrial ROS generation (P<0.05). TP-R-/- mice with RRM lacked these abnormal structural and functional microvascular responses and lacked the increased systemic and the increased microvascular oxidative stress and circulating ET-1. In conclusion, RRM leads to microvascular remodeling and enhanced ET-1-induced cellular and mitochondrial ROS and contractions that are mediated by cyclooxygenase-2 products activating TP-Rs. Thus, TP-Rs can be upstream from enhanced ROS, ET-1, microvascular remodeling, and contractility and may thereby coordinate vascular dysfunction in chronic kidney disease.
心血管疾病在慢性肾脏病中很常见，并且与血管紧张素II、内皮素-1（ET-1）、血栓素A2和活性氧（ROS）有关。由于血栓素类前列腺素受体（TP-Rs）的激活可产生活性氧，而活性氧又可产生内皮素-1，因此我们检验了以下假设：慢性肾脏病可诱导环氧合酶-2，其产物激活TP-Rs以增强内皮素-1和活性氧的生成及收缩。在假手术（SHAM）或手术切除部分肾脏（RRM，每组n = 6）3个月后，从C57/BL6或TP-R+/+和TP-R-/-小鼠分离肠系膜阻力小动脉。在血管张力测定仪上研究微血管收缩。通过荧光显微镜测量细胞内（乙啶：二氢乙啶）和线粒体（mitoSOX）活性氧。RRM小鼠氧化应激、血栓素和微量白蛋白标志物的排泄增加；血浆内皮素-1升高；微血管中p22(phox)、环氧合酶-2、TP-Rs、前内皮素原和内皮素-A受体的表达增加，小动脉重塑增加。它们对U-46,619（118±3对87±6，P<0.05）和内皮素-1（108±5对89±4，P<0.05）的收缩增加，这依赖于细胞和线粒体活性氧、环氧合酶-2和TP-Rs。RRM使内皮素引起的细胞和线粒体活性氧生成增加一倍（P<0.05）。RRM的TP-R-/-小鼠缺乏这些异常的微血管结构和功能反应，且缺乏全身和微血管氧化应激增加以及循环内皮素-1升高。总之，RRM导致微血管重塑以及内皮素诱导的细胞和线粒体活性氧及收缩增强，这是由环氧合酶-2产物激活TP-Rs介导的。因此，TP-Rs可能位于活性氧、内皮素-1、微血管重塑和收缩性增强的上游，从而可能协调慢性肾脏病中的血管功能障碍。
