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

Sci Rep. 2016 Sep 21;6:33678. doi: 10.1038/srep33678.

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.

MeSH terms

  • Aminobutyrates / pharmacology
  • Angiotensin I / metabolism
  • Angiotensin II / genetics
  • Angiotensin II / metabolism
  • Angiotensin-Converting Enzyme 2
  • Animals
  • Biomarkers
  • Biopsy
  • Biphenyl Compounds / pharmacology
  • Female
  • Gene Expression
  • Humans
  • Immunohistochemistry
  • Kidney / physiology*
  • Kidney Cortex / physiology
  • Mice
  • Mice, Knockout
  • Neprilysin / antagonists & inhibitors
  • Neprilysin / metabolism*
  • Peptide Fragments / metabolism
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Renin / genetics
  • Renin / metabolism
  • Renin-Angiotensin System / physiology*

Substances

  • Aminobutyrates
  • Biomarkers
  • Biphenyl Compounds
  • LBQ657
  • Peptide Fragments
  • Angiotensin II
  • Angiotensin I
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2
  • Renin
  • Neprilysin
  • angiotensin I (1-7)