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Title: Cellular mechanisms underlying the ACE inhibitor capacity to stimulate kidney self-repair
Author: Rizzo , Paola
ISNI:       0000 0004 5363 9107
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2014
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Bowman's capsule parietal epithelial cell activation occurs in several human proliferative glomerulonephritides. The cellular composition of the resulting crescentic lesions is controversial, although a population of renal progenitor cells, which in adult healthy kidney contributes to the physiological cell turnover, has been proposed to be a major constituent. In this study we try to get light into the mediators involved in the aberrant progenitor cell proliferation and migration into the Bowman's space, which occurs in presence of an extended glomerular injury. To this aim, we studied 36 renal biopsies of patients with proliferative and non proliferative glomerulopathies. In parallel, we also analyzed the Munich Wistar Fromter rats with proliferative glomerulonephritis, characterizing for the first time a population of renal progenitor cells also in rodents. We demonstrated that dysregulated progenitor cells of the Bowman's capsule invade the glomerular tuft exclusively in proliferative disorders. In both humans and rats, up-regulation . of the CXCR4 chemokine receptor on progenitor cells was accompanied by high expression of its ligand, stromal-derived factor-1 (SDF-1) in podocytes. Parietal epithelial cell proliferation might be sustained by increased expression of the angiotensinII type1 (AT1) receptor. Treatment with the antihypertensive drug angiotensin-converting enzyme (ACE) inhibitor, reduces the number and the extension of crescents, limiting progenitor cell proliferation and migration. Moreover, ACE inhibitor normalized the expression of CXCR4, SDF-1 and ATl receptor on progenitor cells. These results suggest that glomerular crescents derive from the proliferation and migration of renal progenitors in response to injured podocytes. The SDF-1/CXCR4 axis, together with the AngII/ ATl receptor pathway, contributes to the dysregulated response of renal progenitors. Targeting the AngII/ AT1/ CXCR4 pathway may be beneficial in severe forms of glomerular proliferative disorders.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available