Angiotensin-converting enzyme 2 regulates renal atrial natriuretic peptide through angiotensin-(1-7)

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

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)

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. 

Original languageEnglish
Pages (from-to)29-37
Number of pages9
JournalClinical Science
Volume123
Issue number1
DOIs
Publication statusPublished - Jul 2012
Externally publishedYes

Keywords

  • Angiotensin-(1-7)
  • Angiotensin-converting enzyme 2 (ACE2)
  • Atrial natriuretic peptide (ANP)
  • Diabetes
  • Epithelial tubular cell
  • Kidney disease

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