Laboratory of Kidney Disease, Department of Nephrology, Hunan Provincial People's Hospital (The First-Affiliated Hospital of Hunan Normal University), Changsha Clinical Research Center for Kidney Disease, Hunan Clinical Research Center for Chronic Kidney Disease, Changsha 410005, China.
Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
Cells. 2022 Feb 17;11(4):712. doi: 10.3390/cells11040712.
Nephrotoxicity is a major side-effect of cisplatin in chemotherapy, which can occur acutely or progress into chronic kidney disease (CKD). The protein p53 plays an important role in acute kidney injury induced by cisplatin, but its involvement in CKD following cisplatin exposure is unclear. Here, we address this question by using experimental models of repeated low-dose cisplatin (RLDC) treatment. In mouse proximal tubular BUMPT cells, RLDC treatment induced p53 activation, apoptosis, and fibrotic changes, which were suppressed by pifithrin-α, a pharmacologic inhibitor of p53. In vivo, chronic kidney problems following RLDC treatment were ameliorated in proximal tubule-specific p53-knockout mice (PT-p53-KO mice). Compared with wild-type littermates, PT-p53-KO mice showed less renal damage (KIM-1 positive area: 0.97% vs. 2.5%), less tubular degeneration (LTL positive area: 15.97% vs. 10.54%), and increased proliferation (Ki67 positive area: 2.42% vs. 0.45%), resulting in better renal function after RLDC treatment. Together, these results indicate that p53 in proximal tubular cells contributes significantly to the development of chronic kidney problems following cisplatin chemotherapy.
肾毒性是化疗顺铂的主要副作用，可急性发生或进展为慢性肾脏病（CKD）。p53 蛋白在顺铂诱导的急性肾损伤中起重要作用，但它在顺铂暴露后 CKD 中的作用尚不清楚。在这里，我们通过使用重复低剂量顺铂（RLDC）治疗的实验模型来解决这个问题。在小鼠近端肾小管 BUMPT 细胞中，RLDC 处理诱导 p53 激活、细胞凋亡和纤维化改变，这些改变被 p53 药理学抑制剂 pifithrin-α抑制。在体内，RLDC 处理后近端小管特异性 p53 敲除小鼠（PT-p53-KO 小鼠）的慢性肾脏问题得到改善。与野生型同窝仔相比，PT-p53-KO 小鼠的肾脏损伤较小（KIM-1 阳性面积：0.97%比 2.5%），肾小管变性较少（LTL 阳性面积：15.97%比 10.54%），增殖增加（Ki67 阳性面积：2.42%比 0.45%），因此 RLDC 处理后的肾功能更好。综上所述，这些结果表明，顺铂化疗后近端肾小管细胞中的 p53 显著促进慢性肾脏问题的发展。
