Critical Role of Neprilysin in Kidney Angiotensin Metabolism

Circ Res. 2020 Aug 14;127(5):593-606. doi: 10.1161/CIRCRESAHA.119.316151. Epub 2020 May 18.


Rationale: Kidney homeostasis is critically determined by the coordinated activity of the renin-angiotensin system (RAS), including the balanced synthesis of its main effector peptides Ang (angiotensin) II and Ang (1-7). The condition of enzymatic overproduction of Ang II relative to Ang (1-7) is termed RAS dysregulation and leads to cellular signals, which promote hypertension and organ damage, and ultimately progressive kidney failure. ACE2 (angiotensin-converting enzyme 2) and NEP (neprilysin) induce the alternative, and potentially reno-protective axis by enhancing Ang (1-7) production. However, their individual contribution to baseline RAS balance and whether their activities change in chronic kidney disease (CKD) has not yet been elucidated.

Objective: To examine whether NEP-mediated Ang (1-7) generation exceeds Ang II formation in the healthy kidney compared with diseased kidney.

Methods and results: In this exploratory study, we used liquid chromatography-tandem mass spectrometry to measure Ang II and Ang (1-7) synthesis rates of ACE, chymase and NEP, ACE2, PEP (prolyl-endopeptidase), PCP (prolyl-carboxypeptidase) in kidney biopsy homogenates in 11 healthy living kidney donors, and 12 patients with CKD. The spatial expression of RAS enzymes was determined by immunohistochemistry. Healthy kidneys showed higher NEP-mediated Ang (1-7) synthesis than Ang II formation, thus displaying a strong preference towards the reno-protective alternative RAS axis. In contrast, in CKD kidneys higher levels of Ang II were recorded, which originated from mast cell chymase activity.

Conclusions: Ang (1-7) is the dominant RAS peptide in healthy human kidneys with NEP rather than ACE2 being essential for its generation. Severe RAS dysregulation is present in CKD dictated by high chymase-mediated Ang II formation. Kidney RAS enzyme analysis might lead to novel therapeutic approaches for CKD.

Keywords: angiotensin; chymase; kidney; neprilysin; renin-angiotensin system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angiotensin I / metabolism*
  • Angiotensin II / metabolism*
  • Angiotensin-Converting Enzyme 2 / antagonists & inhibitors
  • Angiotensin-Converting Enzyme 2 / metabolism
  • Animals
  • Case-Control Studies
  • Chymases / metabolism
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Kidney / drug effects
  • Kidney / enzymology*
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Neprilysin / antagonists & inhibitors
  • Neprilysin / metabolism*
  • Peptide Fragments / metabolism*
  • Renal Insufficiency, Chronic / enzymology*
  • Renin-Angiotensin System*


  • Enzyme Inhibitors
  • Peptide Fragments
  • Angiotensin II
  • Angiotensin I
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Chymases
  • Neprilysin
  • angiotensin I (1-7)