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| Item Type: | Article |
|---|---|
| Title: | Neprilysin is a mediator of alternative renin-angiotensin-system activation in the murine and human kidney |
| Creators Name: | 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., Säemann, M.D., Linker, R.A. and Poglitsch, M. |
| 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. |
| Keywords: | Aminobutyrates, Angiotensin I, Angiotensin II, Angiotensin II, Biomarkers, Biopsy, Biphenyl Compounds, Gene Expression, Immunohistochemistry, Kidney, Kidney Cortex, Neprilysin, Peptide Fragments, Peptidyl-Dipeptidase A, Renin, Renin-Angiotensin System, Animals, Mice |
| Source: | Scientific Reports |
| ISSN: | 2045-2322 |
| Publisher: | Nature Publishing Group |
| Volume: | 6 |
| Page Range: | 33678 |
| Date: | 21 September 2016 |
| Official Publication: | https://doi.org/10.1038/srep33678 |
| PubMed: | View item in PubMed |
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