Abstract: TH-PO016
Treprostinil Inhibits Apoptosis During Rat Renal Ischemia-Reperfusion Injury
Session Information
- AKI: Mechanisms - Primary Injury and Repair - I
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Ghonem, Nisanne S., University of Rhode Island, Kingston, Rhode Island, United States
- Ding, Meiwen, University of Rhode Island, Kingston, Rhode Island, United States
- Birkenbach, Mark, Rhode Island Hospital, Providence, Rhode Island, United States
- Akhlaghi, Fatemeh, University of Rhode Island, Kingston, Rhode Island, United States
- Gohh, Reginald Y., Rhode Island Hospital, Providence, Rhode Island, United States
Background
Kidney transplantation (KTx) is the optimal treatment for end-stage renal diseases. Ischemia-reperfusion (I/R) injury, an unavoidable process during KTx, is a major cause of delayed graft function, carrying a high mortality rate if patients are not re-transplanted immediately. No pharmacological treatment for I/R injury is available. Treprostinil (Remodulin®), an FDA-approved prostacyclin analog, has potent vasodilatory and anti-platelet aggregatory effects. We recently demonstrated the efficacy of treprostinil in reducing acute kidney injury during bilateral rat renal ischemia. The objective of this study is to determine the inhibitory role of treprostinil on renal apoptosis during rat renal I/R injury.
Methods
Male Sprague Dawley rats were randomly divided into four groups: control, sham, I/R-placebo and I/R-treprostinil groups and subjected to 45 minutes of bilateral renal ischemia followed by reperfusion for 1-168 hours. Placebo or treprostinil (100 ng/kg/min) was administered subcutaneously via an osmic mini-pump. Blood and kidney tissue were collected for analysis.
Results
Treprostinil significantly reduced elevated SCr vs. placebo (0.93 ± 0.17 mg/dl vs. 0.41 ± 0.04 mg/dl, p<0.001) and BUN (150.87 ± 20.38 md/dl vs. 74.06 ± 6.41 mg/dl, p<0.001) at 24 hr post-I/R injury. Treprostinil also reduced renal mRNA expression of kidney injury markers Kim-1 (5.4-fold, p<0.001) and Ngal (8.9-fold, p<0.001) at 48 hr post-I/R injury. Histopathological analysis showed that treprostinil reduced proximal tubular necrosis by 24 hours post-reperfusion. Treprostinil reduced lipid peroxidation byproduct malondialdehyde (7.30 ± 1.43 to 3.84 ± 0.48 µM/mg protein, p<0.05) and renal pro-inflammatory cytokines Ccl2, Il-6 and Il-1β by 2.0- (p<0.05), 2.1- (p<0.01) and 3.3-fold (p<0.001), respectively at 6 hrs post-I/R injury. Additionally, treprostinil reduced protein expression of pro-apoptotic Bax, cleaved caspase-3, and -9 by 1.4- (p<0.05), 1.8- (p<0.05), and 1.3-fold (p<0.05), respectively, at 24 hr after I/R injury.
Conclusion
Our results demonstrate that treprostinil improves renal function and inhibits renal inflammation and apoptosis after renal I/R injury. These results suggest a potential therapeutic application of treprostinil in protecting the kidney against I/R injury during KTx.
Funding
- Other NIH Support