Abstract: PO0346
Treprostinil Improves Mitochondrial Dynamics and Reduces Oxidative Stress During Renal Ischemia-Reperfusion Injury in Rats
Session Information
- AKI: Mechanisms of Injury
November 04, 2021 | Location: On-Demand, Virtual Only
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Ding, Meiwen, University of Rhode Island, Kingston, Rhode Island, United States
- Tolbert, Evelyn, Rhode Island Hospital, Providence, Rhode Island, United States
- Birkenbach, Mark, Rhode Island Hospital, Providence, Rhode Island, United States
- Gohh, Reginald Y., Rhode Island Hospital, Providence, Rhode Island, United States
- Ghonem, Nisanne S., University of Rhode Island, Kingston, Rhode Island, United States
Background
Renal ischemia-reperfusion injury (IRI) is a major factor that contributes to acute kidney injury (AKI). Mitochondria enriched in renal proximal tubular cells are particularly susceptible to IRI-induced oxidative stress. Currently, there is no treatment for IRI available. We recently demonstrated the efficacy of treprostinil (Remodulin®), an FDA-approved prostacyclin analog, in reducing AKI during bilateral rat renal IRI. This study investigates the role of treprostinil in improving mitochondrial dynamics and reducing oxidative stress during rat renal IRI.
Methods
Male Sprague Dawley rats were subjected to 45 minutes of bilateral renal ischemia followed by 1-72 hours reperfusion. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmotic mini-pump. Blood and kidney tissue were collected for analyses.
Results
Treprostinil significantly reduced renal injury and peak elevated serum creatinine from 24- to 6-hours post-reperfusion compared to placebo-treated animals. PAS staining revealed that treprostinil markedly reduced epithelial cell necrosis and partially attenuated apical brush border loss at 6 hours post-IRI vs. placebo, with near reconstitution of normal histology by 48-hours post-reperfusion. Also, treprostinil restored renal antioxidant levels, including catalase, superoxide dismutase activity, and glutathione content vs. placebo (p<0.001). In parallel, treprostinil improved the mRNA expression of Nqo1 and Gclc, that encode NAD(P)H dehydrogenase [quinone] 1 and glutamate-cysteine ligase catalytic subunit (Gclc) to 45% (p<0.05) and 52% (p<0.01) of sham at 48-hour post-IRI vs. placebo. Treprostinil reduced the renal mitochondrial fission proteins Drp1 and Mff by 61% and 44% relative to placebo (p<0.001) and restored the protein expression of mitochondrial fusion marker Sirt3 along with the mRNA expression of Mfn1, Mfn2, and Opa1 to that of sham (vs. placebo, p<0.0001).
Conclusion
Treprostinil reduced renal oxidative stress as well as Drp1-mediated mitochondrial fission and upregulated Sirt3-mediated mitochondrial fusion, thereby improving renal mitochondrial dynamics and protecting against renal IRI. These results support the clinical investigation of treprostinil as a viable therapy to reduce renal IRI.
Funding
- Other NIH Support