Endocrine Abstracts

During maturation of oxytocin (OT) prohormone, several bioactive intermediate molecules are formed. The plasma concentrations of these forms (OT-G; OT-GK and OT-GKR) increase markedly in rat circulation at the end of gestation. At low concentration in the circulation OT stimulates while OT-GKR inhibits diuresis. Since OT and OT-GKR show different effects on the urine flow, we hypothesized that OT-GKR modulates renal action by targeting the V₂ receptor.

Results: The 8-weeks-old Wistar rats were injected (i.e.) with vehicle, OT and OT-GKR or in combinations. OT (10 μmol/kg) increased urine outflow by 40% (P<0.01) and the sodium excretion by 47% (P<0.01). The treatment with 10 μmol/kg of OT-GKR decreased diuresis by 50% (P<0.001), decreased sodium by 50% (P<0.05) and lowered potassium by 42% (P<0.05). OT antagonist (OTA) reduced diuresis and natriuresis exerted by OT, whereas the anti-diuretic effect of OT-GKR was unaffected by OTA. The treatment with V₂ receptor antagonist (V₂A) in the presence and absence of OT induced diuresis, sodium and potassium outflow. The V₂A in the presence of OT-GKR only partially increased diuresis and natriuresis.

Molecular docking showed potent binding energies of OT-GKR to V₂R as well as to OTR. Moreover, the binding affinity of OT-GKR to V₂R in renal sections is almost equivalent to that of AVP. Finally, the cAMP release from CHO cells overexpressing V₂ receptor has been induced by low concentration of AVP (EC50:4.2e-011), the higher concentration of OT (EC50:3.2e-010) and by very high concentration of OT-GKR (EC50:1.1e-006). The OT-GKR potentiated cAMP release when combined with AVP, but blocked cAMP release when combined with OT.

Conclusions: OT-GKR inhibits diuresis and natriuresis exerted by OT, suggesting an auto-regulation of the renal function by the OT/OT-GKR system. This led us to the conclusion that OT-GKR regulates the kidney effects by specific interactions with V₂ receptor.