Affiliation:
1. Department of Biological Sciences and Hull York Medical School, University of Hull, Kingston-upon-Hull, United Kingdom; and
2. Department of Renal Medicine, Hull and East Yorkshire Hospital NHS Trust, and Hull York Medical School, Kingston-upon-Hull, United Kingdom
Abstract
Chronic kidney disease is associated with a unique cardiomyopathy, characterized by a combination of structural and cellular remodeling, and an enhanced susceptibility to ischemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway due to insulin resistance. The susceptibility of the uremic heart to ischemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Uremia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischemia was investigated in vitro in control and uremic hearts ± insulin ± rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by13C-NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immunoprecipitation. Insulin improved postischemic rate pressure product in control but not uremic hearts, [recovered rate pressure product (%), control 59.6 ± 10.7 vs. 88.9 ± 8.5, P < 0.05; uremic 19.3 ± 4.6 vs. 28.5 ± 10.4, P = ns]. Rosiglitazone resensitized uremic hearts to insulin-mediated cardioprotection [recovered rate pressure product (%) 12.7 ± 7.0 vs. 61.8 ± 15.9, P < 0.05]. Myocardial carbohydrate metabolism remained responsive to insulin in uremic hearts. Uremia was associated with increased phosphorylation of Akt (1.00 ± 0.08 vs. 1.31 ± 0.11, P < 0.05) in normoxia, but no change in postischemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased postischemia in uremic hearts ( P < 0.05). Uremia is associated with enhanced susceptibility to ischemia-reperfusion injury and a loss of insulin-mediated cardioprotection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uremic hearts post-ischemia-reperfusion and impaired activation of the reperfusion injury salvage kinase pathway may underlie these findings.
Publisher
American Physiological Society
Cited by
9 articles.
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