Abstract
Chronic kidney disease (CKD) is associated with endothelial dysfunction and accelerated cardiovascular disease, which are largely driven by systemic oxidative stress and inflammation. Oxidative stress and inflammation in CKD are associated with and, in part, due to impaired activity of the cytoprotective transcription factor Nrf2. RTA dh404 is a synthetic oleanane triterpenoid compound which potently activates Nrf2 and inhibits the pro-inflammatory transcription factor NF-κB. This study was designed to test the effects of RTA dh404 on endothelial function, inflammation, and the Nrf2-mediated antioxidative system in the aorta of rats with CKD induced by 5/6 nephrectomy. Sham-operated rats served as controls. Subgroups of CKD rats were treated orally with RTA dh404 (2mg/kg/day) or vehicle for 12 weeks. The aortic rings from untreated CKD rats exhibited a significant reduction in the acetylcholine-induced relaxation response which was restored by RTA dh404 administration. Impaired endothelial function in the untreated CKD rats was accompanied by significant reduction of Nrf2 activity (nuclear translocation) and expression of its cytoprotective target genes, as well as accumulation of nitrotyrosine and upregulation of NAD(P)H oxidases, 12-lipoxygenase, MCP-1, and angiotensin II receptors in the aorta. These abnormalities were ameliorated by RTA dh404 administration, as demonstrated by the full or partial restoration of the expression of all the above analytes to sham control levels. Collectively, the data demonstrate that endothelial dysfunction in rats with CKD induced by 5/6 nephrectomy is associated with impaired Nrf2 activity in arterial tissue, which can be reversed with long term administration of RTA dh404.
Highlights
RTA dh404 did not alter the maximum contraction evoked by PhE or KCl or the concentration–response of PhE, which are all decreased in rats with Chronic kidney disease (CKD)
Acetylcholine enhances nitric oxide (NO) production in endothelial cells, which facilitates vascular smooth muscle relaxation
Endothelial dysfunction in the untreated CKD rats in this study was associated with significant upregulation of NAD(P)H oxidase, a major source of superoxide in the vascular tissue, and accumulation of nitrotyrosine, a major footprint of NO inactivation by superoxide
Summary
Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease, the major cause of mortality in this patient population [1]. A major contributor to cardiovascular disease in CKD is endothelial dysfunction caused by vascular oxidative stress, inflammation, and dysregulation of key pathways, such as the renin-angiotensin aldosterone axes [2]. Endothelial dysfunction in CKD is primarily driven by oxidative stress, which limits bioavailability of nitric oxide (NO) by lowering its production and promoting its inactivation [3]. Oxidative stress reduces NO bioavailability through the reaction of reactive oxygen species (ROS) with NO to generate reactive nitrogen species, namely peroxynitrite [2]. Interventions aimed at alleviation of oxidative stress can reverse endothelial dysfunction and protect against cardiovascular disease. The addition of functional catalase attenuates the oxidative stress-mediated decrease in the contractile response
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