Date of Award

2021

Degree Type

Thesis

Degree Name

Master of Science in Pharmaceutical Sciences

Specialization

Pharmacology

Department

Biomedical and Pharmaceutical Sciences

First Advisor

Nisanne Ghonem

Abstract

Background: Renal ischemia-reperfusion injury (IRI) occurs during kidney transplantation and causes acute kidney injury as well as liver injury. Renal IRI depletes hepatic antioxidants and leads to hepatic inflammation, tissue damage and hepatic dysfunction through Tlr9 upregulation. There is no treatment available for liver injury during renal IRI. This study examines the hepatoprotective role of treprostinil, a prostacyclin analog, during renal IRI.

Methods: Male Sprague-Dawley rats were divided into four groups: control, sham, IRI-placebo, or IRI-treprostinil and subjected to bilateral ischemia (45 minutes) followed by 1-72 hours of reperfusion. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump.

Results: Treprostinil significantly reduced peak serum creatinine, BUN, alanine aminotransferase, and aspartate aminotransferase levels vs. IRI-placebo. Treprostinil also restored hepatic antioxidant levels, including superoxide dismutase (P<0.05), glutathione (P<0.01), catalase (P<0.001), and Gclc mRNA expression (P<0.05), while reducing lipid peroxidation (P<0.05) vs. IRI-placebo. Additionally, treatment with treprostinil significantly reduced elevated Tlr9 mRNA and protein Il-1, Ccl2, Vcam1 and Serpine1 expression found in the IRI-placebo group. Renal IRI resulted in hepatic apoptosis which was inhibited by treprostinil through reduced hepatic nuclear DNA fragmentation, cytochrome c and cleaved caspase-3 protein expression. Treprostinil enhanced hepatic ATP concentrations and mtDNA copy number while improving mitochondrial dynamics by restoring Pgc-1a, significantly upregulating Mfn1, Mfn2, Sirt3 levels, and reducing renal IRI-induced Drp-1 vs. IRI-placebo. Non-targeted semi-quantitative proteomics showed improved oxidative stress indices and ATP subunits in the IRI-treprostinil group vs. IRI-placebo.

Conclusions: Treprostinil improved hepatic function and antioxidant levels, while suppressing the inflammatory response and alleviating Tlr9-mediated apoptotic injury during renal IRI. Our study provides evidence of treprostinil’s hepatoprotective effect, which supports the therapeutic potential of treprostinil in reducing hepatic injury during renal IRI.

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