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Endocrine Abstracts (2016) 41 EP730 | DOI: 10.1530/endoabs.41.EP730

CRCHUM, University of Montreal, Montreal, Que, Canada.


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.

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