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

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

Authors

David J. Semple

Sunil Bhandari

Anne-Marie L. Seymour



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.

Journal Article Type Article
Publication Date Nov 1, 2012
Journal American journal of physiology. Renal physiology
Print ISSN 1931-857X
Electronic ISSN 1522-1466
Publisher American Physiological Society
Peer Reviewed Peer Reviewed
Volume 303
Issue 9
Pages F1275-F1286
APA6 Citation Semple, D. J., Bhandari, S., & Seymour, A. L. (2012). Uremic cardiomyopathy is characterised by loss of the cardioprotective effects of insulin. AJP - Renal Physiology, 303(9), F1275-F1286. doi:10.1152/ajprenal.00048.2012
DOI https://doi.org/10.1152/ajprenal.00048.2012
Publisher URL http://ajprenal.physiology.org/content/303/9/F1275
Copyright Statement © 2018 The American Physiological Society
Additional Information Authors' accepted manuscript of article published in: American journal of physiology. Renal physiology. 2012, v.303, issue 9

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Copyright Statement
© 2018 The American Physiological Society



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