Grignano Maria Antonietta, Gregorini Marilena, Barisione Chiara, Ivaldo Caterina, Verzola Daniela, Rumeo Noemi, Malabarba Stefano, Mimmi Maria Chiara, Montatixe Fonseca Elizabeth Carolina, Viglio Simona, Iadarola Paolo, Islami Tefik, Pattonieri Eleonora Francesca, Ceccarelli Gabriele, Picciotto Daniela, Pratesi Giovanni, Viazzi Francesca, Stea Emma Diletta, Arbustini Eloisa, Esposito Pasquale, Rampino Teresa
Unit of Nephrology, Dialysis and Transplantation, Fondazione I.R.C.C.S. Policlinico San Matteo, 27100 Pavia, Italy.
Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy.
Int J Mol Sci. 2025 Sep 13;26(18):8937. doi: 10.3390/ijms26188937.
Proprotein Convertase Subtilisin/Kexin type 9 PCSK9 inhibitors (PCSK9i) are a novel class of cholesterol-lowering agents that also offer protection against tissue ischemia by reducing apoptosis, pyroptosis, and myocardial infarct size. This study evaluated the effects of the PCSK9 inhibitor PEP 2-8 during hypothermic perfusion (HP) in a rat model of donation after circulatory death (DCD) kidney transplantation. DCD kidneys were perfused at 4 °C for six hours with either Perf-Gen solution alone (control) or Perf-Gen supplemented with PEP 2-8. Glucose and lactate dehydrogenase (LDH) levels were measured at baseline and after six hours (T6h). At T6h, kidneys were evaluated for ischemic injury, tubular cell proliferation, apoptosis, nitrotyrosine (N-Tyr) staining, tissue ATP and LDH levels, and gene expression of PCSK9 and NOX4. Metabolomic profiling was also performed. PEP 2-8 treatment significantly reduced PCSK9 expression, decreased tubular ischemic injury and necrosis, and lowered LDH release. Treated kidneys showed enhanced tubular cell proliferation, reduced apoptosis, and diminished oxidative stress, indicated by decreased N-Tyr staining and NOX4 expression. Energy metabolism was improved, with higher tissue ATP and glucose levels observed in the PEP 2-8 group. Metabolomic analysis further supported the antioxidant effects of PEP 2-8. This is the first study to demonstrate that PEP 2-8 administered during pre-transplant hypothermic perfusion provides renal protection by improving energy metabolism and reducing oxidative stress in the context of ischemic injury.
前蛋白转化酶枯草溶菌素/克新9型（PCSK9）抑制剂（PCSK9i）是一类新型的降胆固醇药物，还可通过减少细胞凋亡、焦亡和心肌梗死面积来预防组织缺血。本研究评估了PCSK9抑制剂PEP 2-8在低温灌注（HP）期间对循环死亡后供肾（DCD）大鼠肾移植模型的影响。将DCD肾在4℃下用单独的Perf-Gen溶液（对照）或添加了PEP 2-8的Perf-Gen溶液灌注6小时。在基线和6小时后（T6h）测量葡萄糖和乳酸脱氢酶（LDH）水平。在T6h时，评估肾脏的缺血性损伤、肾小管细胞增殖、凋亡、硝基酪氨酸（N-Tyr）染色、组织ATP和LDH水平，以及PCSK9和NOX4的基因表达。还进行了代谢组学分析。PEP 2-8治疗显著降低了PCSK9表达，减少了肾小管缺血性损伤和坏死，并降低了LDH释放。治疗后的肾脏显示肾小管细胞增殖增强、凋亡减少，氧化应激减轻，表现为N-Tyr染色和NOX4表达降低。能量代谢得到改善，PEP 2-8组的组织ATP和葡萄糖水平更高。代谢组学分析进一步支持了PEP 2-8的抗氧化作用。这是第一项证明在移植前低温灌注期间给予PEP 2-8可通过改善能量代谢和减少缺血性损伤背景下的氧化应激来提供肾脏保护的研究。
