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

Oliver Domenig, Arndt Manzel, Nadja Grobe, Eva Königshausen, Christopher C. Kaltenecker, Johannes J. Kovarik, Johannes Stegbauer, Susan B. Gurley, Dunja Van Oyen, Marlies Antlanger, Michael Bader, Daisy Motta-Santos, Robson A. Santos, Khalid M. Elased, Marcus D. Saëmann, Ralf A. Linker, Marko Poglitsch

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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.

Original languageEnglish (US)
Article number33678
JournalScientific Reports
Volume6
DOIs
StatePublished - Sep 21 2016

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    Domenig, O., Manzel, A., Grobe, N., Königshausen, E., Kaltenecker, C. C., Kovarik, J. J., Stegbauer, J., Gurley, S. B., Van Oyen, D., Antlanger, M., Bader, M., Motta-Santos, D., Santos, R. A., Elased, K. M., Saëmann, M. D., Linker, R. A., & Poglitsch, M. (2016). Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney. Scientific Reports, 6, [33678]. https://doi.org/10.1038/srep33678