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.
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Research Article|
March 12 2012
Angiotensin-converting enzyme 2 regulates renal atrial natriuretic peptide through angiotensin-(1–7)
Stella Bernardi;
Stella Bernardi
1
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
†Department of Morphology and Embriology, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy
Correspondence: Dr Stella Bernardi (email [email protected]).
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Wendy C. Burns;
Wendy C. Burns
1
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Barbara Toffoli;
Barbara Toffoli
‡Department of Medical, Surgical, Health Sciences, University of Trieste, Ospedale di Cattinara, Strada di Fiume 447, 34149 Trieste, Italy
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Raelene Pickering;
Raelene Pickering
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
†Department of Morphology and Embriology, University of Ferrara, Via Fossato di Mortara 66, 44100 Ferrara, Italy
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Maryio Sakoda;
Maryio Sakoda
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Despina Tsorotes;
Despina Tsorotes
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Edward Grixti;
Edward Grixti
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Elena Velkoska;
Elena Velkoska
§Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3081, Australia
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Louise M. Burrell;
Louise M. Burrell
§Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3081, Australia
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Colin Johnston;
Colin Johnston
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Merlin C. Thomas;
Merlin C. Thomas
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Bruno Fabris;
Bruno Fabris
‡Department of Medical, Surgical, Health Sciences, University of Trieste, Ospedale di Cattinara, Strada di Fiume 447, 34149 Trieste, Italy
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Christos Tikellis
Christos Tikellis
*Baker IDI Heart and Diabetes Research Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Publisher: Portland Press Ltd
Received:
August 11 2011
Revision Received:
January 24 2012
Accepted:
January 30 2012
Accepted Manuscript online:
January 30 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 123 (1): 29–37.
Article history
Received:
August 11 2011
Revision Received:
January 24 2012
Accepted:
January 30 2012
Accepted Manuscript online:
January 30 2012
Citation
Stella Bernardi, Wendy C. Burns, Barbara Toffoli, Raelene Pickering, Maryio Sakoda, Despina Tsorotes, Edward Grixti, Elena Velkoska, Louise M. Burrell, Colin Johnston, Merlin C. Thomas, Bruno Fabris, Christos Tikellis; Angiotensin-converting enzyme 2 regulates renal atrial natriuretic peptide through angiotensin-(1–7). Clin Sci (Lond) 1 July 2012; 123 (1): 29–37. doi: https://doi.org/10.1042/CS20110403
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