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

Published

Journal Article

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.

Full Text

Cited Authors

  • Domenig, O; Manzel, A; Grobe, N; Königshausen, E; Kaltenecker, CC; Kovarik, JJ; Stegbauer, J; Gurley, SB; van Oyen, D; Antlanger, M; Bader, M; Motta-Santos, D; Santos, RA; Elased, KM; Säemann, MD; Linker, RA; Poglitsch, M

Published Date

  • September 21, 2016

Published In

Volume / Issue

  • 6 /

Start / End Page

  • 33678 -

PubMed ID

  • 27649628

Pubmed Central ID

  • 27649628

Electronic International Standard Serial Number (EISSN)

  • 2045-2322

International Standard Serial Number (ISSN)

  • 2045-2322

Digital Object Identifier (DOI)

  • 10.1038/srep33678

Language

  • eng