Praliciguat alleviates ferroptosis and inflammation in renal ischemia/reperfusion injury by targeting the AMPK/ACC/PUFA pathway

Abstract

Objective: To investigate the reno-protective effects of praliciguat in a rat model of renal ischemia/reperfusion injury (IRI), focusing on its modulation of the AMPK/ACC/PUFA pathway, ferroptosis, and inflammation.

Methods: Twenty-four male Sprague-Dawley rats were randomly assigned to four groups (n = 6): sham, IRI, vehicle (DMSO), and praliciguat (3 mg/kg orally at 24 h and 1 h before ischemia). Renal IRI was induced by bilateral pedicle clamping for 40 minutes, followed by 2 hours of reperfusion. Blood and kidney tissues were collected at the end of reperfusion. Serum urea, creatinine, and NGAL levels, and renal tissue levels of interleukin-1β (IL-1β), AMPK, ACC, and PUFA were assessed. Statistical analysis was performed using one-way ANOVA with Tukey’s post-hoc test.

Results: Compared to the IRI group, praliciguat significantly reduced serum urea (10.8 ± 1.4 vs. 19.6 ± 2.1 mmol/L, p = 0.0012), creatinine (122 ± 13 vs. 212 ± 18 µmol/L, p = 0.0027), and NGAL (88 ± 10 vs. 154 ± 12 ng/mL, p = 0.0039). It also lowered IL-1β (82 ± 9 vs. 136 ± 11 pg/mg, p = 0.0017), ACC (2.1 ± 0.3 vs. 3.6 ± 0.3 ng/mg, p = 0.0014), and PUFA (2.6 ± 0.3 vs. 4.8 ± 0.4 ng/mg, p = 0.0010), while restoring AMPK activity (1.14 ± 0.11 vs. 0.68 ± 0.10 ng/mg, p = 0.0022).

Conclusion: Praliciguat significantly attenuates renal IRI by enhancing AMPK activity and reducing ferroptosis and inflammation. These findings support its potential as a therapeutic agent in acute kidney injury and kidney transplantation.