Kidney Week

Abstract: TH-PO0150

Treprostinil Improves Renal Blood Flow and Function During Renal Ischemia-Reperfusion Injury Through IP/cAMP/PKA Signaling

Session Information

• AKI: Mechanisms - 1
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Acute Kidney Injury

• 103 AKI: Mechanisms

Authors

• Oladepo, Mariam Olaide, University of Rhode Island, Kingston, Rhode Island, United States

Mariam Olaide Oladepo, MSc

• Ding, Meiwen, University of Rhode Island, Kingston, Rhode Island, United States

Meiwen Ding, PhD

• Kazal, Frances H., Brown University, Providence, Rhode Island, United States

Frances H. Kazal

• Birkenbach, Mark, Brown University Health, Providence, Rhode Island, United States

Mark Birkenbach, MD

• Tolbert, Evelyn, Brown University Health, Providence, Rhode Island, United States

Evelyn Tolbert, MBBS

• Ko, Dicken S. c., Brown University Health, Providence, Rhode Island, United States

Dicken S. c. Ko, MD

• Gohh, Reginald Y., Brown University Health, Providence, Rhode Island, United States

Reginald Y. Gohh, MD

• Ghonem, Nisanne S., University of Rhode Island, Kingston, Rhode Island, United States

Nisanne S. Ghonem, PharmD, PhD

Background

Renal ischemia-reperfusion injury (IRI) is a significant contributor to acute kidney injury and delayed graft function after kidney transplantation, with no treatment available. We previously demonstrated the efficacy of treprostinil (Remodulin®), an FDA-approved prostacyclin (PGI₂) analog, in reducing renal IRI in vivo. This study investigates the renal blood flow and reno-protective mechanisms of treprostinil against renal IRI in vivo.

Methods

Male Sprague Dawley rats were randomly divided into four groups: sham, IRI-placebo, IRI-treprostinil low-dose (10 ng/kg/min), or high-dose (100 ng/kg/min). Treprostinil was administered subcutaneously at the time of ischemia or ~18-24 hr before renal IRI. All IRI groups were subjected to bilateral renal IRI (45 mins) followed by reperfusion up to 48 hr (n=4-6 animals/per group).

Results

Compared to placebo, treprostinil (100 ng/kg/min) reduced peak serum creatinine by 60% (2.6 vs. 1.2 mg/dl, P<0.05), and necrotic tubules in the outer medulla by 50% (P<0.05) at 24 hr post-reperfusion. In a dose-dependent manner, cortical and medullary renal blood flow were restored to 100% of baseline by treprostinil compared to 80% by placebo (P<0.01), independent of the timing of administration. Also, treprostinil (100 ng/kg/min) improved creatinine clearance by 2-fold (8.0 vs. 3.9 ml/min/100g), while reducing urinary protein and sodium concentration by 50% (13.1 vs. 23.4 mg/day/100g, and 0.6 vs. 1.3 mmol/day, respectively) vs. placebo (P<0.05). Mechanistically, renal IRI increased renal protein expression of thromboxane (TXA) receptor by 4-fold, while reducing prostacyclin (IP) receptor by 50% and renal cAMP levels by 30 % vs. sham (P<0.05). Conversely, treprostinil reduced TXA expression by 1.5-fold (P=0.08) while restoring IP expression and cAMP levels to that of baseline vs. placebo (P<0.01). Finally, treprostinil increased renal protein kinase A phosphorylation by 3-fold vs. sham (P<0.01).

Conclusion

Treprostinil improves renal blood flow and kidney function early post-reperfusion via activation of IP/cAMP/PKA signaling in a clinically relevant rat model of renal IRI. These findings support the clinical investigation of treprostinil as a novel therapy to reduce renal IRI during kidney transplantation.

Funding

• Other NIH Support – United Therapeutics, Corp.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025qacw4y1y