Alterations in Autophagy and Senescence in the Pathologically Aged Uraemic Heart
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Abstract There is much observational evidence to suggest that patients with chronic kidney disease are biologically ‘older’ than their unaffected peers. This is most obviously seen with cardiovascular disease: young patients on haemodialysis have a relative risk of cardiovascular mortality similar to that of people over 50 years their senior in the general population. Moreover, there are striking analogies between the effects of physiological ageing and uraemia on the structure and function of the heart and vasculature. Despite this, little work has been published looking at whether these similarities are reflected at a molecular and cellular level. Two processes implicated in ageing are autophagy and senescence. There is much inferred evidence that these processes are affected by chronic kidney disease. The aim of this work was to investigate whether autophagy and senescence are indeed altered in the uraemic heart, whether these processes might be linked, and whether the findings of these enquiries might suggest their involvement in the pathogenesis of the prematurely aged cardiac phenotype. An in vitro model of the uraemic myocardium was created using rat cardiac myoblast cells exposed to the uraemic toxin indoxyl sulphate, and in vivo models using adenine-diet and subtotal (5/6) nephrectomy rodents. Autophagy was assayed using immunoblotting, PCR array, immunohistochemistry and fluorescence microscopy, and senescence by immunoblotting and as part of an ageing-dedicated PCR array. Though not achieving statistical significance, markers of autophagy activity appeared to be increased in rat cardiac myoblast cells exposed to indoxyl sulfate, and in cardiac tissue from adenine-diet rats. Interestingly markers of autophagy activity were significantly increased in hepatic tissue from subtotal nephrectomy rats. PCR of RNA purified from cardiac tissue from adenine-diet rats demonstrated an expression of ageing-related genes analogous to that in physiological ageing. Though limited by numbers, these findings present evidence to suggest that autophagy may be upregulated as a protective mechanism in the progeroid uraemic heart, a situation possibly comparable to that in physiological ageing. Changes in cardiac autophagy and ageing in uraemia present new avenues for translational research into pathological ageing in chronic kidney disease.
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