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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.

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


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.

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