Stasi Alessandra, Franzin Rossana, Sallustio Fabio, Scagliotti Alessandro, Cappello Paola, Squiccimarro Elena, Caggiano Gianvito, Losapio Rosa, Campioni Monica, Castellaneta Antonino, Cantaluppi Vincenzo, Curci Claudia, Pontrelli Paola, Stallone Giovanni, Gesualdo Loreto, Fanelli Vito, Castellano Giuseppe
Nephrology, Dialysis and Transplantation Unit, DiMePRe-J, University of Bari "Aldo Moro", Piazza G. Cesare 11, Bari, 70124, Italy.
Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center "Guido Tarone", University of Turin, Turin, Italy.
Sci Rep. 2025 Mar 20;15(1):9635. doi: 10.1038/s41598-025-93815-7.
Sepsis-induced acute kidney injury (AKI) can lead to chronic renal dysfunction with accelerated renal aging. Activation of the mammalian target of rapamycin (mTOR) is implicated in the initiation and progression of renal injury. This study investigates the effectiveness of the mTOR inhibitor, rapamycin, in mitigating kidney injury and explores the underlying mechanisms. AKI was induced by intraperitoneal administration of a solution containing 10 mg/kg of lipopolysaccharide (LPS) in a mouse model. Two groups of endotoxemic mice received pre- and post- treatment with rapamycin. Whole-genome DNA methylation analysis was performed on renal proximal tubular epithelial cells (RPTEC). In the LPS-induced AKI mouse model, rapamycin treatment significantly reduced creatinine levels, preserved renal parenchyma, and counteracted the endothelial-to-mesenchymal transition (EndMT) by inhibiting the ERK pathway. Whole-genome DNA methylation analysis revealed that LPS induced aberrant methylation, particularly in genes associated with premature aging, including ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1/CD39) and wolframin ER transmembrane glycoprotein (WFS1). Accordingly, endotoxemic mice exhibited decreased CD39 expression and klotho down-regulation, both of which were reversed by rapamycin, suggesting an anti-aging effect in AKI. mTOR inhibition may represent a promising strategy to prevent accelerated renal aging in LPS-induced AKI and potentially slow the progression of chronic kidney disease.
脓毒症诱导的急性肾损伤（AKI）可导致慢性肾功能障碍并加速肾脏衰老。雷帕霉素靶蛋白（mTOR）的激活与肾损伤的起始和进展有关。本研究调查了mTOR抑制剂雷帕霉素减轻肾损伤的有效性，并探索其潜在机制。在小鼠模型中，通过腹腔注射含10 mg/kg脂多糖（LPS）的溶液诱导AKI。两组内毒素血症小鼠接受雷帕霉素的预处理和后处理。对肾近端小管上皮细胞（RPTEC）进行全基因组DNA甲基化分析。在LPS诱导的AKI小鼠模型中，雷帕霉素治疗显著降低肌酐水平，保留肾实质，并通过抑制ERK途径对抗内皮-间充质转化（EndMT）。全基因组DNA甲基化分析显示，LPS诱导异常甲基化，特别是在与早衰相关的基因中，包括胞外核苷三磷酸二磷酸水解酶1（ENTPD1/CD39）和沃尔弗拉姆内质网跨膜糖蛋白（WFS1）。因此，内毒素血症小鼠表现出CD39表达降低和klotho下调，两者均被雷帕霉素逆转，提示其对AKI具有抗衰老作用。抑制mTOR可能是一种有前景的策略，可预防LPS诱导的AKI中肾脏加速衰老，并可能减缓慢性肾脏病的进展。
