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Kidney Week

Abstract: PO0164

Kidney Functional Improvements by a Novel Potent and Selective Vasopressin V1a Antagonist After Ischemia/Reperfusion Injury (I/RI) in Rats

Session Information

  • AKI Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

  • 103 AKI: Mechanisms

Authors

  • Droebner, Karoline, Bayer AG, Wuppertal, Germany
  • Cernecka, Hana, Bayer AG, Wuppertal, Germany
  • Fuerstner, Chantal, Bayer AG, Wuppertal, Germany
  • Collin, Marie-Pierre Laure, Bayer AG, Wuppertal, Germany
  • Pavkovic, Mira, Bayer AG, Wuppertal, Germany
  • Hein, Peter, Bayer AG, Wuppertal, Germany
  • Eitner, Frank, Bayer AG, Wuppertal, Germany
  • Kolkhof, Peter, Bayer AG, Wuppertal, Germany
Background

Alteration in renal perfusion is a key pathologic mechanism implicated in the development of ischemic acute kidney injury (AKI). We have reported that activation of V1a receptor decreases renal blood flow (RBF) and oxygenation in settings of increased vasopressin (AVP) levels. Here we studied the role of BAY 2327949, a recently identified potent and selective V1a antagonist, in a rat renal I/RI model.

Methods


In a first setting, rats were infused with BAY 2327949 (100 µg/min/kg i.v.) or vehicle and baseline measurements were determined for 20 min. Unilateral ischemia was induced by clamping of left kidneys for 15 min, followed by 20 min of reperfusion. RBF and intrarenal oxygenation (pO2) were continuously measured via Laser Doppler Flowmetry. In a second setting, kidney function (creatinine, cystatin C, urea) was studied 24h after 45 minutes of ischemia in uninephrectomised male rats treated with BAY 2327949 (0.5, 1 and 3 mg/kg BID, i.v.).

Results


Unilateral clamping resulted in an immediate drop of RBF and pO2 that partially recovered during reperfusion (figure). Treatment with BAY 2327949 significantly ameliorated the severity of ischemic hypoxia and resulted in an improved and almost complete restoration of RBF and pO2 during reperfusion (figure). In the second setting, preventive treatment with BAY 2327949 resulted in dose-dependent, significant improvements of kidney function parameters 24h post I/RI as compared to placebo treated rats.

Conclusion


BAY 2327949 is a novel potent and selective vasopressin V1a receptor antagonist blocking the detrimental effects of elevated vasopressin levels on renal perfusion and oxygenation. For these reasons, BAY 2327949 could become a viable treatment option in conditions of increased AVP levels, such as AKI and CKD.

Funding

  • Commercial Support