Department of Radiation Oncology, Sylvester Comprehensive Cancer Center/Miller School of Medicine, University of Miami, Miami, FL, USA.
Peggy and Harold Katz Family Drug Discovery Center and Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami, Miami, FL, USA.
Radiother Oncol. 2023 Oct;187:109813. doi: 10.1016/j.radonc.2023.109813. Epub 2023 Jul 17.
Radiation nephropathy (RN) can be a severe late complication for patients treated with radiotherapy (RT) targeting abdominal and paraspinal tumors. Recent studies investigating the mechanisms of RT-mediated injury in the kidney have demonstrated that RT disrupts the cellular integrity of renal podocytes leading to cell death and loss of renal function.
To determine if RT-induced renal dysfunction is associated with alterations in podocyte and glomerular function, and whether RT-induced podocyte alterations were associated with changes in the glomerular basement membrane (GBM).
C57BL/6 mice were treated with focal bilateral X-irradiation using a single dose (SD) of 4 Gy, 10 Gy, or 14 Gy or fractionated dosing (FD) of 5x6Gy or 24x2Gy. Then, 10-40 weeks after RT parameters of renal function were measured, along with glomerular filtration rate (GFR) and glomerular histology, as well as ultrastructural changes in GBM by transmission electron microscopy.
RT treatment resulted in persistent changes in renal function beginning at 10 weeks with little recovery up to 40 weeks post RT. Dose dependent changes were seen with increasing SD but no functional sparing was evident after FD. RT-induced loss of renal function was associated with expansion of the GBM and significant increases in foot process width, and associated with significant reduction in GFR, podocyte loss, and renal fibrosis.
For the first time, these data show that expansion of the GBM is one consequence of radiation injury, and disarrangement of the GBM might be associated with the death of podocytes. These data shed new light on the role podocyte injury and GBM in RT-induced renal dysfunction.
放射性肾病（RN）是接受腹部和脊柱旁肿瘤放射治疗（RT）的患者的一种严重的迟发性并发症。最近研究表明，RT 破坏了肾足细胞的细胞完整性，导致细胞死亡和肾功能丧失，从而发现了 RT 介导的肾损伤机制。
确定 RT 诱导的肾功能障碍是否与足细胞和肾小球功能的改变有关，以及 RT 诱导的足细胞改变是否与肾小球基底膜（GBM）的变化有关。
使用单次剂量（SD）4 Gy、10 Gy 或 14 Gy 或分次剂量（FD）5x6Gy 或 24x2Gy，对 C57BL/6 小鼠进行双侧 X 射线照射。然后，在 RT 参数后 10-40 周测量肾功能，肾小球滤过率（GFR）和肾小球组织学，以及透射电镜检查 GBM 的超微结构变化。
RT 治疗导致肾功能持续变化，从 10 周开始，到 RT 后 40 周几乎没有恢复。随着 SD 的增加观察到剂量依赖性变化，但 FD 后没有功能节省。RT 诱导的肾功能丧失与 GBM 的扩张以及足突宽度的显著增加有关，与 GFR、足细胞丢失和肾纤维化的显著减少有关。
这些数据首次表明，GBM 的扩张是放射损伤的后果之一，GBM 的排列紊乱可能与足细胞的死亡有关。这些数据为足细胞损伤和 GBM 在 RT 诱导的肾功能障碍中的作用提供了新的见解。
