Alterations in Autophagy and Senescence in the Pathologically Aged Uraemic Heart
Publisher
Metadata
Show full item recordAbstract
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.
Authors
White, WilliamCollections
- Theses [4099]