Thromboxane prostanoid receptors enhance contractions, endothelin-1, and oxidative stress in microvessels from mice with chronic kidney disease.

Abstract

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.

• Authors: Cheng Wang, Zaiming Luo, Donald Kohan, Anton Wellstein, Pedro A Jose, William J Welch, Christopher S Wilcox, Dan Wang
• Journal: Hypertension (Dallas, Tex. : 1979) (Hypertension) Vol. 65 Issue 5 Pg. 1055-63 (May 2015) ISSN: 1524-4563 [Electronic] United States
• PMID: 25733239 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Endothelin-1
• Reactive Oxygen Species
• Receptors, Thromboxane
• RNA

Topics

• Animals
• Arterioles (metabolism, physiopathology)
• Disease Models, Animal
• Endothelin-1 (biosynthesis, genetics)
• Gene Expression Regulation
• Kidney (blood supply)
• Male
• Mice
• Mice, Inbred C57BL
• Oxidative Stress
• RNA (genetics)
• Reactive Oxygen Species (metabolism)
• Real-Time Polymerase Chain Reaction
• Receptors, Thromboxane (biosynthesis, genetics)
• Renal Circulation
• Renal Insufficiency, Chronic (genetics, metabolism, physiopathology)
• Vascular Remodeling
• Vasoconstriction