Date of Award
Doctor of Philosophy in Pharmaceutical Sciences
Pharmacology and Toxicology
Biomedical and Pharmaceutical Sciences
Renal ischemia-reperfusion injury (IRI) occurs in a variety of clinical settings, including sepsis, cardiac bypass, shock, or kidney transplantation. Renal IRI is often unavoidable and is a major cause of morbidity and mortality for this diverse set of patients. However, no pharmacological treatments for prevention or amelioration of renal IRI are available.
Renal IRI is a multifactorial process and a major cause of acute kidney injury (AKI). During renal IRI, the initial decline in tissue oxygen reduces oxidative phosphorylation and depletes intracellular ATP stores, ultimately leading to mitochondria damage and disruption of renal tubular epithelial cell structure. One of the early and major targets of renal IRI is the depletion of adenosine triphosphate (ATP), which disrupts mitochondria structure and function. As the master energy producer enriched in renal proximal tubular cells, mitochondria play a central role in kidney function. Disruption of mitochondria initiates oxidative injury, causing apoptosis, necrosis, and inflammation with an associated rapid onset of renal dysfunction.
Prostacyclin (PGI2) is a member of the prostaglandin family with potent vasodilatory and anti-platelet actions approximately 30 times more potent than prostaglandin E1. A key step in promoting reperfusion-related injury has been attributed to a decreased ratio in vasodilatory mediators such as PGI2, relative to vasoconstrictor mediators such as thromboxane. The role of PGI2 in increasing renal blood flow has been demonstrated in animal renal failure and clinical studies. However, while PGI2 analogs have been tested for their renoprotective effects, poor chemical stability side effects of earlier analogs and short half-lives necessitating continuous infusion have limited their clinical application during AKI. Treprostinil (Remodulin®), an FDA-approved PGI2 analog, is stable at room temperature, has an increased potency and longer elimination half-life than other commercially available PGI2 analogs, which allow for lower and more tolerable dosing to achieve therapeutic efficacy, and fewer side effects.
In this dissertation, we demonstrated the renoprotective effects of treprostinil during renal IRI using a rat model of bilateral renal IRI. These findings showed that treprostinil improved renal function, reduced proinflammatory cytokines, chemokines, adhesion molecules, oxidative stress, and apoptosis, thereby accelerating recovery from renal IRI in vivo.
Furthermore, we identified a novel mechanism of treprostinil in reducing mitochondrial injury during renal IRI. Specifically, our data showed that treprostinil maintained mitochondrial homeostasis via inhibiting Drp-1-mediated mitochondrial fission and Erk1/2 phosphorylation and upregulating mitochondrial Sirt3 and Pgc-1a to promote mitochondrial fusion and biogenesis, thereby counteracting mitochondrial damage early post-renal IRI.
In addition to the molecular mechanisms of IRI-induced AKI, the hemodynamics of the kidney vasculature remains a vital aspect of the renal IRI process. As a highly perfused organ, changes to renal blood flow render the kidney particularly vulnerable to IRI and significantly impact kidney function. To parallel the clinical setting and availability of treatment more closely for the patient, we compared the efficacy of two treatment models with treprostinil: before the ischemia (pre-treatment) and at the time of ischemia. We demonstrated that treatment with treprostinil at the time of renal ischemia and at 18-24 hours pre-ischemia both effectively improved renal hemodynamics and kidney function, evidenced by remarkedly increased renal blood flow and GFR, and reduced sodium excretion and proteinuria.
Collectively, the significance of this study is in providing data to support treprostinil, an FDA-approved PGI2 analog, as a potential therapy for reducing renal IRI, which would be beneficial to improve long-term kidney function, for which no treatment is available.
Ding, Meiwen, "TREPROSTINIL, A PROSTACYCLIN ANALOG, PROTECTS KIDNEY FROM RENAL ISCHEMIA-REPERFUSION INJURY: PRECLINICAL STUDIES IN A RAT MODEL OF ACUTE KIDNEY INJURY" (2022). Open Access Dissertations. Paper 1375.