Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, Korea.
Subtropical/Tropical Organism Gene Bank, Jeju National University, Jeju 63243, Korea.
Cells. 2022 Nov 2;11(21):3472. doi: 10.3390/cells11213472.
Cisplatin is a potent chemotherapeutic used for the treatment of many types of cancer, but it has nephrotoxic side effects leading to acute kidney injury and subsequently chronic kidney disease (CKD). Previous work has focused on acute kidney tubular injury induced by cisplatin, whereas the chronic sequelae post-injury has not been well-explored. In the present study, we established a kidney fibroblast model of CKD induced by repeated administration of cisplatin (RAC) as a clinically relevant model. In NRK-49F rat kidney fibroblasts, RAC upregulated α-smooth muscle actin (α-SMA) and fibronectin proteins, suggesting that RAC induces kidney fibroblast-to-myofibroblast transformation. RAC also enhanced cell size, including the cell attachment surface area, nuclear area, and cell volume. Furthermore, RAC induced p21 expression and senescence-associated β-galactosidase activity, suggesting that kidney fibroblasts exposed to RAC develop a senescent phenotype. Inhibition of p21 reduced cellular senescence, hypertrophy, and myofibroblast transformation induced by RAC. Intriguingly, after RAC, kidney fibroblasts were arrested at the G2/M phase. Repeated treatment with paclitaxel as an inducer of G2/M arrest upregulated p21, α-SMA, and fibronectin in the kidney fibroblasts. Taken together, these data suggest that RAC transforms kidney fibroblasts into myofibroblasts through G2/M arrest and cellular senescence.
顺铂是一种有效的化疗药物，用于治疗多种类型的癌症，但它有肾毒性副作用，导致急性肾损伤，进而导致慢性肾脏病（CKD）。以前的工作集中在顺铂引起的急性肾小管损伤上，而损伤后的慢性后果尚未得到很好的探索。在本研究中，我们建立了重复给予顺铂（RAC）诱导的 CKD 肾成纤维细胞模型，作为一种临床相关的模型。在 NRK-49F 大鼠肾成纤维细胞中，RAC 上调了α-平滑肌肌动蛋白（α-SMA）和纤维连接蛋白蛋白，表明 RAC 诱导肾成纤维细胞向肌成纤维细胞转化。RAC 还增强了细胞大小，包括细胞附着表面积、核面积和细胞体积。此外，RAC 诱导 p21 表达和衰老相关的β-半乳糖苷酶活性，表明暴露于 RAC 的肾成纤维细胞表现出衰老表型。抑制 p21 减少了 RAC 诱导的细胞衰老、肥大和肌成纤维细胞转化。有趣的是，RAC 后，肾成纤维细胞停滞在 G2/M 期。重复用紫杉醇作为 G2/M 期阻滞诱导剂处理肾成纤维细胞，上调了 p21、α-SMA 和纤维连接蛋白。综上所述，这些数据表明 RAC 通过 G2/M 期阻滞和细胞衰老将肾成纤维细胞转化为肌成纤维细胞。
