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

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: Domenig O, Manzel A, Grobe N, Koenigshausen E, Kaltenecker CC, Kovarik JJ, Stegbauer J, Gurley SB, Van Oyen D, Antlanger M, Bader M, Motta-Santos D, Santos RA, Elased KM, Saeemann MD, Linker R, Poglitsch M
Zeitschrift: Scientific Reports
Jahr der Veröffentlichung: 2016
Band: 6
Seitenbereich: 33678
ISSN: 2045-2322


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.



FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Linker, Ralf PD Dr.
Stiftungsprofessur für Neuroimmunologie


Einrichtungen weiterer Autorinnen und Autoren

Attoquant Diagnostics GmbH
Duke University
Heinrich-Heine-Universität Düsseldorf
Max-Delbrück-Centrum für Molekulare Medizin (MDC) Berlin-Buch
Medizinische Universität Wien
Universidade Federal de Minas Gerais (UFMG)
Wright State University


Zitierweisen

APA:
Domenig, O., Manzel, A., Grobe, N., Koenigshausen, E., Kaltenecker, C.C., Kovarik, J.J.,... Poglitsch, M. (2016). Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney. Scientific Reports, 6, 33678. https://dx.doi.org/10.1038/srep33678

MLA:
Domenig, Oliver, et al. "Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney." Scientific Reports 6 (2016): 33678.

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Zuletzt aktualisiert 2019-28-02 um 06:07