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dc.contributor.authorL'Huillier, Nathalieen
dc.date.accessioned2018-03-29T12:18:16Z
dc.date.available2018-03-29T12:18:16Z
dc.date.issued2007
dc.identifier.urihttp://hdl.handle.net/1842/29224
dc.description.abstracten
dc.description.abstractThe renin-angiotensin system (RAS) is a key biochemical pathway controlling homeostasis and blood pressure. The initial step of the RAS is carried out by renin to produce angiotensin (Ang) I which is converted to Angll by the angiotensin-converting enzyme (ACE). Renin is synthesized as a pro-enzyme which can be activated in dense core granules of the renal juxtaglomerular cells or released as prorenin. There is evidence that prorenin can, in addition, be activated in a reversible manner, via a prorenin receptor. Recently, a specific (pro)renin receptor was identified in human tissues. Binding ofthis receptor to (pro)renin caused increased cleavage of angiotensinogen and stimulation of an intracellular signalling pathway. The aim of this thesis is to investigate the biology of prorenin, its maturation and the (pro)renin receptor.en
dc.description.abstractExpression of the mouse putative (pro)renin receptor (RR) was detected by RT-PCR in all tissues and cell lines examined including human mesangial cells previously reported to be negative for RR. Mouse RR was also present during development from E9.5. The mouse and rat RR cDNA were found to be highly homologous (92% and 91%, respectively) to the human cDNA. Surprisingly, the translated human, mouse and rat cDNAs exhibited sequence identity with a small protein co-purifying with a bovine vacuolar-ATPase called M8-9 which had not been reported previously. V-ATPases are critical for cell survival. Phylogenic studies revealed RR is highly conserved between species and likely to be important physiologically. The role of RR was investigated in a high circulating prorenin rat model [TGR(Cyplal-Ren2)], in which (pro)renin triggers malignant hypertension (MH).en
dc.description.abstractUptake of prorenin by the heart previously demonstrated in this transgenic model may be mediated by RR. In the present study, the animals, from a new colony, had a gradual hypertensive response. Cardiovascular stiffening was measured using echo(cardio)graphy. Despite an obvious hypertrophic remodeling and longer exposure to the inducer, no signs of microinfarctions or inflammatory infiltration cells were observed in the heart. Fibrinoid necrosis of small intra-renal vessels with glomerulosclerosis and mesenteric artery remodeling were also observed. The phenotype differs from the original work. Surprisingly, RR was not up-regulated. The reasons for the phenotypic differences between TGR(Cyplal-Ren2) colonies were examined. Two main observations were made: dietary sodium levels appear to correlate with the severity of MH and TGR(Cyplal-Ren2) animals reported in this thesis had a lower pathogen load.en
dc.description.abstractTo investigate the possible role of RR, a prorenin decoy peptide was used to attempt to ameliorate the MH phenotype in TGR(Cyplal-Ren2) animals. This peptide which competes with prorenin for binding to RR, has been showed to improve vascular injuries in diabetic nephropathy. In TGR(Cyplal-Ren2), however, no changes in the MH phenotype could be observed, except in the mesentery in which less severe fibrinoid necrosis developed.en
dc.description.abstractTo complement work on RR, prorenin maturation and renin storage were studied during development. The data showed the complete absence of renin granules in mouse kidneys before birth. This indicates that renin could not be stored and may not be processed through the regulated pathway as observed in the adult. Low sodium diet and ACE inhibition triggered (pro)renin granules to be produced in the foetal kidney. Two ACE inhibitors differing in their ability to cross the placenta were used. The data suggest that foetal renin granule formation is under dual control from both foetal and maternal RAS.en
dc.description.abstractAlthough the (pro)renin receptor may be important physiologically, the data presented in this thesis suggest a more fundamental role in cell biology than had previously been recognised. The lack of evidence for regulation of RR in a model of high prorenin and malignant hypertension suggests that the function of this protein may need to be re-assessed.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2018 Block 17en
dc.relation.isreferencedbyAlready catalogueden
dc.titleProrenin, its maturation and the (pro)renin receptoren
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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