Treprostinil alleviates hepatic mitochondrial injury during rat renal ischemia-reperfusion injury

• Published in: Biomedicine & pharmacotherapy Vol. 143; p. 112172
• Main Authors: Hou, Joyce, Tolbert, Evelyn, Birkenbach, Mark, Ghonem, Nisanne S.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-11-2021; Elsevier
• Subjects: Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Anti-Inflammatory Agents - pharmacology; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Disease Models, Animal; Energy Metabolism - drug effects; Epoprostenol - analogs & derivatives; Epoprostenol - pharmacology; Hepatitis - metabolism; Hepatitis - pathology; Hepatitis - prevention & control; Inflammation; Inflammation Mediators - metabolism; Lipid Peroxidation - drug effects; Liver - drug effects; Liver - metabolism; Liver - pathology; Liver injury; Male; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondria, Liver - pathology; Mitochondrial Dynamics - drug effects; Oxidative stress; Oxidative Stress - drug effects; Prostacyclin; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Signal Transduction; Toll-Like Receptor 9 - metabolism; IRI; Oxidative stress; mtDNA; Cox-IV; Gsta2; ALT; SWATH-MS; Prostacyclin; MDA; 18S; mt-Nd1; Gpx; Gstm4; Gclc; TUNEL; Mfn; Drp-1; Ccl2; BUN; TLR; GSH; AKI; AST; IL; SCr; PGI2; H&E; SOD; Inflammation; Gapdh; Liver injury; Vcam1; CAT; ROS; Sirt3; Serpine1; ATP; Pgc-1α; Apoptosis
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112172

Renal ischemia-reperfusion injury (IRI) causes acute kidney injury as well as liver injury. Renal IRI depletes hepatic antioxidants, promotes hepatic inflammation and 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.
Male Sprague-Dawley rats were divided into four groups: control, sham, IRI-placebo, or IRI-treprostinil and subjected to bilateral ischemia (45 min) followed by reperfusion (1–72 h). Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump.
Treprostinil significantly reduced peak serum creatinine, BUN, ALT and AST levels vs. IRI-placebo. Treprostinil also restored hepatic levels of superoxide dismutase, glutathione, catalase, and Gclc expression to baseline, while reducing lipid peroxidation vs. IRI-placebo. Additionally, treprostinil significantly reduced elevated hepatic Tlr9, Il-1β, Ccl2, Vcam1, and Serpine1 mRNA expression. Renal IRI increased hepatic apoptosis which was inhibited by treprostinil through reduced cytochrome c and cleaved caspase-3 protein expression. Treprostinil enhanced hepatic ATP concentrations and mitochondrial DNA copy number and improved mitochondrial dynamics by restoring Pgc-1α expression and significantly upregulating Mfn1, Mfn2, and Sirt3 levels, while reducing Drp-1 protein vs. IRI-placebo. Non-targeted semi-quantitative proteomics showed improved oxidative stress indices and ATP subunits in the IRI-treprostinil group.
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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•Hepatic injury occurs during renal IRI and increases in-hospital mortality, there is no treatment available.•Treprostinil inhibits renal IRI-induced hepatic inflammation and mitochondrial-mediated apoptosis in vivo.•Treprostinil is a novel and viable treatment to ameliorate renal IRI-induced hepatic injury.