Thromboxane Prostanoid Receptors Enhance Contractions, Endothelin-1, and Oxidative Stress in Microvessels From Mice With Chronic Kidney Disease

Abstract

Cardiovascular disease (CVD) is frequent in chronic kidney disease (CKD) and has been related to angiotensin II (ANG II), endothelin-1 (ET-1), thromboxane A2 (TxA2) and reactive oxygen species (ROS). Since activation of thromboxane prostanoid receptors (TP-Rs) can generate ROS which can generate ET-1, we tested the hypothesis that CKD induces cyclooxygenase (COX)-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 p22phox, COX-2, TP-Rs, preproendothelin and endothelin-A receptors and increased arteriolar remodeling. They had increased contractions to U-46,619 (118±3 vs. 87±6, P<0.05) and ET-1 (108±5 vs. 89±4, P<0.05), which were dependent on cellular and mitochondrial ROS, COX-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 COX-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 CKD.

Mitochondrial Fission Inhibitors Suppress Endothelin-1-Induced Artery Constriction

“…Most studies considered that ET-1-induced generation of ROS in the vascular smooth muscle cells were from mitochondria[43, 44]. We found that the mitochondria-targeted antioxidant, mitoTEMPO, inhibited ET-1-induced constriction of rat mesenteric arteries, confirming ET-1-induced mitochondria-derived ROS.…”

Coronary microvascular disease as an early culprit in the pathophysiology of diabetes and metabolic syndrome

“…Indeed, ROS was shown to be involved in remodeling mediated by growth factors such as platelet-derived growth factor (PDGF) and transforming growth factor-β (TGF-β). Finally, the role of mitochondrial ROS in mediateding microvascular remodeling in mesenteric arteriols was also observed in reduced renal mass hypertension model (67). …”

The role of eicosanoids in renal diseases – potential therapeutic possibilities

“…PGE 2 plays an important role in CKD mainly via both, EP 2 and 4 receptors. (Wang et al, 2015) Mice Chronic kidney disease predisposes to cardiovascular accidents because of increased concentration of TXA 2. (Wang et al, 2007) Mice PGI2 plays an important protective role in AKI caused by endotoxemia, by improving the function of kidneys in PGI2-cAMP-renin pathway.…”

“…It has been highlighted in mice studies that the chronic kidney disease predisposes to cardiovascular accidents because of increased concentration of TXA 2 which activates its receptors and contributes to the generation of reactive oxygen species (ROS). This results in bigger endothelial activation, leads to microvascular remodeling and might be the reason of cardiovascular accidents (Wang et al, 2015). Another study on mice had shown that TXA2 is an important agent in decreasing the renal function in the model of lupus nephritis.…”