Thromboxane prostanoid receptors enhance contractions, endothelin-1 and oxidative stress in microvessels from mice with CKD
| Autor: | Wang, Cheng, Luo, Zaiming, Kohan, Donald, Wellstein, Anton, Jose, Pedro A., Welch, William J., Wilcox, Christopher S., Wang, Dan |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Endothelin-1 Receptors Thromboxane Vascular Remodeling Kidney Real-Time Polymerase Chain Reaction Article Renal Circulation Mice Inbred C57BL Arterioles Disease Models Animal Mice Oxidative Stress Gene Expression Regulation Vasoconstriction Animals RNA Renal Insufficiency Chronic Reactive Oxygen Species |
| Popis: | 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, P0.05) and ET-1 (108 ± 5 versus 89 ± 4, P0.05), which were dependent on cellular and mitochondrial ROS, cyclooxygenase-2, and TP-Rs. RRM doubled the ET-1-induced cellular and mitochondrial ROS generation (P0.05). 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. |
| Databáze: | OpenAIRE |
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