Effect of exercise training on aortic tone in chronic renal insufficiency.

BACKGROUND: Chronic renal insufficiency (CRI) is associated with a high incidence of hypertension (HTN), endothelial dysfunction, atherosclerosis and cardiovascular disease. Sedentary life style increases, whereas regular exercise reduces the risk of cardiovascular disease. This study was designed to test the effect of regular exercise on vasodilatory and vasoconstrictive responses of the thoracic aorta in rats with renal mass reduction. METHODS: One week after 5/6 nephrectomy (CRI) or sham operation (control), rats were housed in either regular cages or cages equipped with running wheels for 4 weeks. Thereafter, thoracic aorta was harvested and contractile response to potassium and phenylephrine (PhE), and relaxation response to acetylcholine (ACh) and sodium nitroprusside (SNP) were determined. RESULTS: Compared with the control animals, sedentary CRI animals exhibited significant azotemia, proteinuria, HTN, oxidative stress, and increased sensitivity to potassium and PhE, and reduced sensitivity to ACh and SNP. Exercise training for 4 weeks reduced oxidative stress, reversed CRI-induced heightened sensitivity of the aorta to PhE and potassium, and restored its sensitivity to ACh (but not SNP) without affecting arterial pressure or renal function. CONCLUSIONS: CRI results in heightened sensitivity to potassium- and alpha-1 adrenergic-mediated contractility and depressed sensitivity to endothelium-dependent relaxation in the aorta. Regular exercise improves these abnormalities without affecting arterial pressure or renal function. These observations suggest that exercise training can improve vascular function in animals, and perhaps humans, with chronic kidney disease.

The synthetic triterpenoid RTA dh404 (CDDO-dhTFEA) restores endothelial function impaired by reduced Nrf2 activity in chronic kidney disease.

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 (2 mg/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.