Thromboxane prostanoid receptors enhance contractions, endothelin-1, and oxidative stress in microvessels from mice with chronic kidney disease.
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.
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.).
Cheng
C
Wang
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.).
Zaiming
Z
Luo
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.).
Donald
D
Kohan
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.).
Anton
A
Wellstein
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.).
Pedro A
PA
Jose
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.).
William J
WJ
Welch
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.).
Christopher S
CS
Wilcox
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.). dw32@georgetown.edu.
Dan
D
Wang
D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation; D007668:Kidney / Q000098:blood supply*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D012313:RNA / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017482:Receptors, Thromboxane / Q000096:biosynthesis* / Q000235:genetics; D012079:Renal Circulation; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D066253:Vascular Remodeling; D014661:Vasoconstriction
D019332:Endothelin-1; D017382:Reactive Oxygen Species; D017482:Receptors, Thromboxane; D012313:RNA
cyclooxygenase; mitochondria; oxidative stress; thromboxane; vascular remodeling