González-Nicolás María Ángeles, Humanes Blanca, Herrero Raquel, Arenillas Mario, López Beatriz, Ferruelo Antonio, Lorente José Ángel, Lázaro Alberto
Renal Physiopathology Laboratory, Department of Nephrology, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, 28007 Madrid, Spain.
Department of Physiology, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain.
Int J Mol Sci. 2025 Aug 16;26(16):7927. doi: 10.3390/ijms26167927.
Sepsis is a life-threatening condition caused by an abnormal host response to infection, leading to organ dysfunction and potentially death. Acute kidney injury (AKI) is a critical complication of sepsis. Various pathways, especially signaling through Toll-like receptors (TLRs) and the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome, contribute to inflammation and tissue damage. Cilastatin, a renal dehydropeptidase I inhibitor, has shown promise in protecting against AKI induced by nephrotoxic drugs. This study assessed cilastatin's effectiveness in preventing AKI and inflammation caused by sepsis and its impact on survival. Sepsis was induced in male rats using the cecal ligation puncture (CLP) model, with four groups: sham (control), CLP, sham + cilastatin, and CLP + cilastatin. Cilastatin (150 mg/kg) was administered immediately and 24 h after sepsis induction. Kidney injury was evaluated 48 h later by assessing serum creatinine, blood urea nitrogen, glomerular filtration rate, proteinuria, kidney injury molecule-1 levels, and renal morphology. Inflammatory and fibrotic biomarkers, particularly related to the TLR4 and NLRP3 pathways, were also measured. Cilastatin treatment prevented kidney dysfunction, reduced inflammatory markers, and improved survival by 33%. These results suggest that cilastatin could be a beneficial therapeutic strategy for sepsis-related AKI, improving outcomes and reducing mortality.
脓毒症是一种由宿主对感染的异常反应引起的危及生命的病症，可导致器官功能障碍甚至死亡。急性肾损伤（AKI）是脓毒症的一种关键并发症。多种途径，尤其是通过Toll样受体（TLR）以及含核苷酸结合寡聚化结构域、富含亮氨酸重复序列和吡啉结构域的蛋白3（NLRP3）炎性小体的信号传导，会导致炎症和组织损伤。西司他丁是一种肾脱氢肽酶I抑制剂，已显示出对预防肾毒性药物诱导的急性肾损伤有一定作用。本研究评估了西司他丁在预防脓毒症引起的急性肾损伤和炎症方面的有效性及其对生存率的影响。使用盲肠结扎穿刺（CLP）模型在雄性大鼠中诱导脓毒症，分为四组：假手术组（对照组）、CLP组、假手术 + 西司他丁组和CLP + 西司他丁组。在脓毒症诱导后立即及24小时给予西司他丁（150 mg/kg）。48小时后通过评估血清肌酐、血尿素氮、肾小球滤过率、蛋白尿、肾损伤分子-1水平及肾脏形态来评估肾损伤。还测量了炎症和纤维化生物标志物，特别是与TLR4和NLRP3途径相关的标志物。西司他丁治疗可预防肾功能障碍，降低炎症标志物，并使生存率提高33%。这些结果表明，西司他丁可能是治疗脓毒症相关急性肾损伤的有益治疗策略，可改善预后并降低死亡率。
