title: Angiotensin-converting enzyme 2 regulates renal atrial natriuretic peptide through angiotensin-(1-7).
abstract: Deficiency of ACE2 (angiotensin-converting enzyme 2), which degrades Ang (angiotensin) II, promotes the development of glomerular lesions. However, the mechanisms explaining why the reduction in ACE2 is associated with the development of glomerular lesions have still to be fully clarified. We hypothesized that ACE2 may regulate the renoprotective actions of ANP (atrial natriuretic peptide). The aim of the present study was to investigate the effect of ACE2 deficiency on the renal production of ANP. We evaluated molecular and structural abnormalities, as well as the expression of ANP in the kidneys of ACE2-deficient mice and C57BL/6 mice. We also exposed renal tubular cells to AngII and Ang-(1-7) in the presence and absence of inhibitors and agonists of RAS (renin-angiotensin system) signalling. ACE2 deficiency resulted in increased oxidative stress, as well as pro-inflammatory and profibrotic changes. This was associated with a down-regulation of the gene and protein expression on the renal production of ANP. Consistent with a role for the ACE2 pathway in modulating ANP, exposing cells to either Ang-(1-7) or ACE2 or the Mas receptor agonist up-regulated ANP gene expression. This work demonstrates that ACE2 regulates renal ANP via the generation of Ang-(1-7). This is a new mechanism whereby ACE2 counterbalances the renal effects of AngII and which explains why targeting ACE2 may be a promising strategy against kidney diseases, including diabetic nephropathy.
authors.affiliation: Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia. stella.bernardi@bakeridi.edu.au
authors.forename: Stella
authors.initials: S
authors.lastname: Bernardi
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Burns
authors.forename: Barbara
authors.initials: B
authors.lastname: Toffoli
authors.forename: Raelene
authors.initials: R
authors.lastname: Pickering
authors.forename: Maryio
authors.initials: M
authors.lastname: Sakoda
authors.forename: Despina
authors.initials: D
authors.lastname: Tsorotes
authors.forename: Edward
authors.initials: E
authors.lastname: Grixti
authors.forename: Elena
authors.initials: E
authors.lastname: Velkoska
authors.forename: Louise M
authors.initials: LM
authors.lastname: Burrell
authors.forename: Colin
authors.initials: C
authors.lastname: Johnston
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
authors.forename: Bruno
authors.initials: B
authors.lastname: Fabris
authors.forename: Christos
authors.initials: C
authors.lastname: Tikellis
mesh_terms: D000803:Angiotensin I / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000378:metabolism*; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D012084:Renin-Angiotensin System / Q000502:physiology
chemical_list: D010446:Peptide Fragments; D000804:Angiotensin II; D009320:Atrial Natriuretic Factor; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7)