Glover, Zoe (2017) Acer, a homologue of the human angiotensin-1 converting enzyme, modulates the response of sleep, glycogen storage, lifespan, fecundity and stress resistance to diet in Drosophila melanogaster. PhD thesis, UNSPECIFIED.
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Abstract
Human angiotensin-1–converting-enzyme (ACE) plays a primary role in the regulation of blood pressure and electrolytes as part of the Renin-Angiotensin System (RAS) in humans. Renin cleaves angiotensinogen to angiotensin I and ACE regulates the vasoconstriction of blood vessels by converting angiotensin-1 to angiotensin-2 (a potent vasoconstrictor) and also by breaking down bradykinin (a potent vasodilator). Renin is regulated by a feedback loop mechanism and is inhibited by higher concentrations of angiotensin-2. A lack of or inhibition of ACE can lead to a reduction in blood pressure (BP) and may reduce the risk of diabetic nephropathy as high BP and high fluid retention can cause swelling in the kidneys. ACE inhibitors are used as treatments for these conditions as well as treating congestive heart failure (Stanley & Samson, 2002). ACE expression has been found in human adipose cells (Jonsson, et al., 1994) and ACE expression in this tissue was reduced when rats were treated with the ACE inhibitor Enalapril (Santos, et al., 2009). Currently ACE’s role in this tissue is unknown and therefore the study of the Drosophila homolog ACER, which is expressed within the fly fat body which is similar in structure to human adipose cells, may highlight a role for ACE in adipose tissue. To investigate the role of ACE-like enzymes in dietary effects on ageing-related and circadian health, function and metabolism we are studying ACER, a homologue of human ACE, in the fruit fly Drosophila melanogaster. Previous studies (Taylor, et al., 1996; Carhan, et al., 2010) have shown that Acer is expressed in the embryonic heart, adult head and adult fat body of the fly. The expression in the fat body is particularly interesting as the fly fat body acts like the human liver and adipose cells where ACE in humans is expressed. Acer’s expression in the head shows a circadian cycle and appears to be regulated by the circadian gene Clock. AcerΔ mutant flies exhibit normal circadian locomotor rhythms but show defects in the regulation of sleep, and the ACE inhibitor, Fosinopril, fed to flies disrupts night time sleep in the same way. This suggests a role for ACER in a circadian phenotypes in Drosophila and therefore a potential circadian role for ACE in humans (Carhan, et al., 2010). The present study has found the effect of the loss of Acer expression in the Acer deletion mutant (AcerΔ) was complex and was often dependent on genetic background and sex. AcerΔ mutants responded normally to dietary restriction (DR) for both sex and background therefore, Acer was not required for the DR response to lifespan. Lipid storage in the AcerΔ mutants was unaffected by the loss of Acer expression but glycogen storage was reduced on high food levels and did not show the normal increase in storage with increasing food compared to controls. Thus, indicating a role for Acer in the modulation of glycogen storage. The genetic backgrounds analysed in this study were the outbred whiteDahomey (wDah) and inbred white1118 (w1118) backgrounds which did show a difference in the effect of the loss of Acer for certain phenotypes. Fecundity in AcerΔ females was lower than in controls in the more fecund wDah background but not in the less fecund w1118 background. Sleep also showed an altered response between the backgrounds and sexes to changing diet in AcerΔ mutants. AcerΔ mutants were starvation and oxidative stress resistant but only in the wDah background and showed sensitivity when compared to controls in the w1118 background. To investigate Acer’s role in the response to nutrition the effect of the loss of Acer on drosophila-insulin-like peptides (dilps) was investigated. Altered transcript levels of dilps in the head and body of the fly in AcerΔ mutants indicated a possible link between Acer and the IIS (insulin/IGF-like signalling) nutrient-sensing pathway. In this study a role for Acer in the modulation of nutrient responsive phenotypes was established.