Azzam Patrick, Francis Marina, Youssef Tarek, Mroueh Manal, Daher Alaa Abou, Eid Assaad A, Fornoni Alessia, Marples Brian, Zeidan Youssef H
Department of Anatomy, Cell Biology, and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
Peggy and Harold Katz Family Drug Discovery Center and Division of Nephrology, Department of Medicine, University of Miami, Miami, FL, United States.
Front Med (Lausanne). 2021 Sep 29;8:732528. doi: 10.3389/fmed.2021.732528. eCollection 2021.
Patients undergoing radiotherapy (RT) for various tumors localized in the abdomen or pelvis often suffer from radiation nephrotoxicity as collateral damage. Renal podocytes are vulnerable targets for ionizing radiation and contribute to radiation-induced nephropathies. Our prior work previously highlighted the importance of the lipid-modifying enzyme sphingomyelinase acid phosphodiesterase like 3b (SMPDL3b) in modulating the radiation response in podocytes and glomerular endothelial cells. Hereby, we investigated the interplay between SMPDL3b and oxidative stress in mediating radiation injury in podocytes. We demonstrated that the overexpression of SMPDL3b in cultured podocytes (OE) reduced superoxide anion generation and NADPH oxidase activity compared to wild-type cells (WT) post-irradiation. Furthermore, OE podocytes showed downregulated levels of NOX1 and NOX4 after RT. On the other hand, treatment with the NOX inhibitor GKT improved WTs' survival post-RT and restored SMPDL3b to basal levels. , the administration of GKT restored glomerular morphology and decreased proteinuria in 26-weeks irradiated mice. Taken together, these results suggest a novel role for NOX-derived reactive oxygen species (ROS) upstream of SMPDL3b in modulating the response of renal podocytes to radiation.
接受腹部或盆腔局部各种肿瘤放射治疗（RT）的患者常因附带损伤而遭受放射性肾毒性。肾足细胞是电离辐射的敏感靶点，并导致放射性肾病。我们之前的工作曾强调脂质修饰酶酸性磷酸二酯酶样鞘磷脂酶3b（SMPDL3b）在调节足细胞和肾小球内皮细胞辐射反应中的重要性。在此，我们研究了SMPDL3b与氧化应激在介导足细胞辐射损伤中的相互作用。我们证明，与照射后的野生型细胞（WT）相比，培养的足细胞中SMPDL3b过表达（OE）减少了超氧阴离子的产生和NADPH氧化酶活性。此外，照射后OE足细胞中NOX1和NOX4水平下调。另一方面，用NOX抑制剂GKT处理可提高WT照射后的存活率，并使SMPDL3b恢复到基础水平。此外，给予GKT可恢复26周照射小鼠的肾小球形态并减少蛋白尿。综上所述，这些结果表明，在调节肾足细胞对辐射的反应中，NOX衍生的活性氧（ROS）在SMPDL3b上游具有新作用。
