Introduction: Renal ischemia-reperfusion injury (IRI) is a crucial factor causing acute kidney injury (AKI). To date, no pharmacological treatments are available for the prevention of I/R-induced renal injury. Here, we investigate the renal hemodynamics and reno-protective effects of the prostacyclin analog, treprostinil, against renal IRI in vivo.
Methods: Male Sprague Dawley rats were subjected to bilateral renal ischemia (45 minutes) followed by reperfusion (1–48 hour). Treprostinil (100 ng/kg/min) was administered subcutaneously either (A) at the time of ischemia (IRI-immT) or (B) approximately 18-24 hours before renal IRI (IRI-preT).
Results: Serum and urine creatinine were elevated at 24 hours post-reperfusion in the IRI group vs. sham (P <0.001), which both the IRI-immT and IRI-preT reduced the peak of serum creatinine at 24 hours after renal IRI (P <0.001). Also, medullary and cortical renal blood flow (RBF) were significantly reduced in the IRI group vs. sham (P < 0.001), whereas the IRI-immT (P < 0.01) and IRI-preT (P < 0.05) groups improved RBF at 90 minutes post-reperfusion and maintained throughout 120 minutes. In parallel, animals in the IRI injury group experienced a decreased eGFR , increased urinary sodium (UNa 2+) excretion and proteinuria during the first 24 hours post-reperfusion vs. sham (P < 0.01). Meanwhile, treprostinil reduced the UNa 2+ and proteinuria and completely restored the eGRF to baseline by 48 hours post-reperfusion and , compared to the IRI group (P <0.01).
Conclusions: This study demonstrates the efficacy of treprostinil in improving renal hemodynamics and kidney function early post-IRI in a clinically relevant rat model of AKI. Specifically, our data show that treprostinil remarkably increased renal blood flow and GFR, and reduced sodium excretion and proteinuria post-reperfusion. Importantly, these data suggest that treprostinil has the potential to serve as a therapeutic agent to protect the kidney against renal IRI.
Source of Funding: Funding support for this project was provided in part by the Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health, which funds the University of Rhode Island Core Lab (P20GM103430). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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