Treprostinil reduces mitochondrial injury during rat renal ischemia-reperfusion injury

• Published in: Biomedicine & pharmacotherapy Vol. 141; p. 111912
• Main Authors: Ding, Meiwen, Tolbert, Evelyn, Birkenbach, Mark, Gohh, Reginald, Akhlaghi, Fatemeh, Ghonem, Nisanne S.
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.09.2021
• Subjects: Acute kidney injury; Acute Kidney Injury - drug therapy; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Animals; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Epoprostenol - analogs & derivatives; Epoprostenol - pharmacology; Epoprostenol - therapeutic use; Kidney - blood supply; Kidney - drug effects; Kidney - metabolism; Kidney - pathology; Male; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Oxidative Stress - drug effects; Oxidative Stress - physiology; Prostacyclin; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; IRI; PAS; mtDNA; Cox IV; SWATH-MS; Prostacyclin; Mff; Drp1; Gclc; Mitochondria; TUNEL; Opa1; Mfn1; Mfn2; GSH; AKI; Nqo1; SCr; PGI2; Acute kidney injury; SOD; pErk1/2; CAT; Sirt3; Pgc-1α; Apoptosis
• ISSN: 0753-3322; 1950-6007; 1950-6007
• DOI: 10.1016/j.biopha.2021.111912

Renal ischemia-reperfusion injury (IRI) is a major factor contributing to acute kidney injury and it is associated with a high morbidity and mortality if untreated. Renal IRI depletes cellular and tissue adenosine triphosphate (ATP), which compromises mitochondrial function, further exacerbating renal tubular injury. Currently, no treatment for IRI is available. This study investigates the protective role of treprostinil in improving mitochondria biogenesis and recovery during rat renal IRI. Male Sprague Dawley rats were randomly assigned to groups: control, sham, IRI-placebo or IRI-treprostinil and subjected to 45 min of bilateral renal ischemia followed by 1–72 h reperfusion. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic minipump. Treprostinil significantly reduced peak elevated serum creatinine (SCr) levels and accelerated normalization relative to IRI-placebo (p < 0.0001). Treatment with treprostinil also inhibited IRI-mediated renal apoptosis, mitochondrial oxidative injury (p < 0.05), and the release of cytochrome c (p < 0.01) vs. IRI-placebo. In addition, treprostinil preserved renal mitochondrial DNA copy number (p < 0.0001) and renal ATP levels (p < 0.05) to nearly those of sham-operated animals. Non-targeted semi-quantitative proteomics showed reduced levels of ATP synthase subunits in the IRI-placebo group which were restored to sham levels by treprostinil treatment (p < 0.05). Furthermore, treprostinil reduced renal IRI-induced upregulated Drp1 and pErk protein levels, and restored Sirt3 and Pgc-1α levels to baseline (p < 0.05). Treprostinil reduces mitochondrial-mediated renal apoptosis, inhibits mitochondria fission, and promotes mitochondria fusion, thereby accelerating mitochondrial recovery and protecting renal proximal tubules from renal IRI. These results support the clinical investigation of treprostinil as a viable therapy to reduce renal IRI. [Display omitted] •What is already known about this subject: Renal IRI significantly contributes to mortality in AKI, no treatment is available.•What this study adds: Treprostinil inhibits renal IRI-induced mitochondrial injury and apoptosis in vivo.•Clinical significance: Treprostinil is a novel and viable treatment to ameliorate renal IRI-induced AKI.