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

Publication ,  Journal Article
Domenig, O; Manzel, A; Grobe, N; Königshausen, E; Kaltenecker, CC; Kovarik, JJ; Stegbauer, J; Gurley, SB; van Oyen, D; Antlanger, M; Bader, M ...
Published in: Scientific reports
September 2016

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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Published In

Scientific reports

DOI

EISSN

2045-2322

ISSN

2045-2322

Publication Date

September 2016

Volume

6

Start / End Page

33678

Related Subject Headings

  • Renin-Angiotensin System
  • Renin
  • Peptidyl-Dipeptidase A
  • Peptide Fragments
  • Neprilysin
  • Mice, Knockout
  • Mice
  • Kidney Cortex
  • Kidney
  • Immunohistochemistry
 

Citation

APA
Chicago
ICMJE
MLA
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Domenig, O., Manzel, A., Grobe, N., Königshausen, 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://doi.org/10.1038/srep33678
Domenig, Oliver, Arndt Manzel, Nadja Grobe, Eva Königshausen, Christopher C. Kaltenecker, Johannes J. Kovarik, Johannes Stegbauer, et al. “Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney.Scientific Reports 6 (September 2016): 33678. https://doi.org/10.1038/srep33678.
Domenig O, Manzel A, Grobe N, Königshausen E, Kaltenecker CC, Kovarik JJ, et al. Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney. Scientific reports. 2016 Sep;6:33678.
Domenig, Oliver, et al. “Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney.Scientific Reports, vol. 6, Sept. 2016, p. 33678. Epmc, doi:10.1038/srep33678.
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. Neprilysin is a Mediator of Alternative Renin-Angiotensin-System Activation in the Murine and Human Kidney. Scientific reports. 2016 Sep;6:33678.

Published In

Scientific reports

DOI

EISSN

2045-2322

ISSN

2045-2322

Publication Date

September 2016

Volume

6

Start / End Page

33678

Related Subject Headings

  • Renin-Angiotensin System
  • Renin
  • Peptidyl-Dipeptidase A
  • Peptide Fragments
  • Neprilysin
  • Mice, Knockout
  • Mice
  • Kidney Cortex
  • Kidney
  • Immunohistochemistry