Uremic cardiomyopathy is characterised by loss of the cardioprotective effects of insulin

Semple, David J.; Bhandari, Sunil; Seymour, Anne-Marie L.

Abstract

Chronic kidney disease is associated with a unique cardiomyopathy, characterised by a combination of structural and cellular remodelling, and an enhanced susceptibility to ischaemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway, due to insulin resistance. Aims: The susceptibility of the uraemic heart to ischaemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Methods and Results: Uraemia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischaemia was investigated in vitro in control and uraemic hearts ±insulin ±rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by 13C NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immuno-precipitation. Insulin improved post-ischaemic rate pressure product in control but not uraemic hearts, (recovered rate pressure product (%), control 59.6±10.7 vs 88.9±8.5, p<0.05; uraemic 19.3±4.6 vs 28.5±10.4, p=ns). Rosiglitazone resensitised uraemic hearts to insulin-mediated cardio-protection (recovered rate pressure product (%) 12.7±7.0 vs. 61.8±15.9, p<0.05). Myocardial carbohydrate metabolism remained responsive to insulin in uraemic hearts. Uraemia 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 post-ischaemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased post-ischaemia in uraemic hearts (p<0.05). Conclusion: Uraemia is associated with enhanced susceptibility to ischaemia-reperfusion injury and a loss of insulin-mediated cardio-protection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uraemic hearts post ischaemia-reperfusion and impaired activation of reperfusion injury salvage kinase pathway may underlie these findings.

Citation

Semple, D. J., Bhandari, S., & Seymour, A.-M. L. (2012). Uremic cardiomyopathy is characterised by loss of the cardioprotective effects of insulin. AJP - Renal Physiology, 303(9), F1275-F1286. https://doi.org/10.1152/ajprenal.00048.2012

• Journal Article Type: Article
• Acceptance Date: Aug 21, 2012
• Online Publication Date: Nov 1, 2012
• Publication Date: Nov 1, 2012
• Deposit Date: Nov 13, 2014
• Publicly Available Date: Nov 23, 2017
• Journal: American journal of physiology. Renal physiology
• Print ISSN: 1931-857X
• Publisher: American Physiological Society
• Peer Reviewed: Peer Reviewed
• Volume: 303
• Issue: 9
• Pages: F1275-F1286
• DOI: https://doi.org/10.1152/ajprenal.00048.2012
• Public URL: https://hull-repository.worktribe.com/output/467521
• Publisher URL: http://ajprenal.physiology.org/content/303/9/F1275
• Additional Information: Authors' accepted manuscript of article published in: American journal of physiology. Renal physiology. 2012, v.303, issue 9
• Contract Date: Nov 23, 2017