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Sci Rep. 2016 Sep 21;6:33678. doi: 10.1038/srep33678.

Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney.

Author information

1
Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
2
Department of Neurology, University Hospital Erlangen, Erlangen, Germany.
3
Department of Pharmacology and Toxicology, Wright State University, OH, USA.
4
Department of Nephrology, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany.
5
Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, NC 27710, USA.
6
Attoquant Diagnostics GmbH, Vienna, Austria.
7
Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, Germany.
8
Department of Physiology and Biophysics, National Institute of Science and Technology in Nanobiopharmaceutics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
9
Institute of Cardiology, University Cardiology Foundation, Porto Alegre, RS, Brazil.

Abstract

Cardiovascular and renal pathologies are frequently associated with an activated renin-angiotensin-system (RAS) and increased levels of its main effector and vasoconstrictor hormone angiotensin II (Ang II). Angiotensin-converting-enzyme-2 (ACE2) has been described as a crucial enzymatic player in shifting the RAS towards its so-called alternative vasodilative and reno-protective axis by enzymatically converting Ang II to angiotensin-(1-7) (Ang-(1-7)). Yet, the relative contribution of ACE2 to Ang-(1-7) formation in vivo has not been elucidated. Mass spectrometry based quantification of angiotensin metabolites in the kidney and plasma of ACE2 KO mice surprisingly revealed an increase in Ang-(1-7), suggesting additional pathways to be responsible for alternative RAS activation in vivo. Following assessment of angiotensin metabolism in kidney homogenates, we identified neprilysin (NEP) to be a major source of renal Ang-(1-7) in mice and humans. These findings were supported by MALDI imaging, showing NEP mediated Ang-(1-7) formation in whole kidney cryo-sections in mice. Finally, pharmacologic inhibition of NEP resulted in strongly decreased Ang-(1-7) levels in murine kidneys. This unexpected new role of NEP may have implications for the combination therapy with NEP-inhibitors and angiotensin-receptor-blockade, which has been shown being a promising therapeutic approach for heart failure therapy.

PMID:
27649628
PMCID:
PMC5030486
DOI:
10.1038/srep33678
[Indexed for MEDLINE]
Free PMC Article

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