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 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. However, their contribution to baseline RAS balance and whether their activities change in chronic kidney disease (CKD) has not yet been elucidated.

To examine whether NEP-mediated Ang (1–7) generation exceeds Ang II formation in the healthy kidney compared with diseased kidney. 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. In contrast, in CKD kidneys, higher levels of Ang II were recorded, which originated from mast cell chymase activity. Ang (1–7) is the dominant RAS peptide in healthy human kidneys, with NEP rather than ACE2 essential for its generation.

In conclusion, our results demonstrate that healthy human kidneys display a strong alternative RAS activity with pronounced NEP-mediated generation of Ang (1–7) compared with a moderate Ang II formation derived from classical RAS activity. Finally, our results indicate that NEP is the critical enzyme for kidney Ang (1–7) formation both in healthy human kidney tissue and CKD. These results help better understand the homeostatic regulation of the intrarenal RAS in health and disease with potential implications for future innovative therapeutic strategies.