Characterizing Cisplatin-Induced Chronic Kidney Disease: Insight from a Model of Myofibroblast Transformation in Kidney Fibroblasts

Cisplatin is a potent chemotherapeutic agent used to treat various types of cancer. However, its use is associated with a nephrotoxic side effect, which can lead to acute kidney injury (AKI) and subsequent chronic kidney disease (CKD). Previous research has primarily focused on AKI caused by cisplatin, while the long-term consequences post-injury have not been thoroughly investigated. Furthermore, a recent clinical study found that most cancer patients face lasting kidney damage after repeated administration of cisplatin (RAC) at low doses. In this study, a model of CKD in kidney fibroblasts induced by RAC was established to mimic clinically relevant conditions. In NRK-49F rat kidney fibroblasts, RAC increased the expression of
-smooth muscle actin (
-SMA; F=11.564, p<0.001, n=4) and fibronectin proteins (F=9.846, p=0.001, n=4), indicating that RAC triggers the transformation of kidney fibroblasts into myofibroblasts. RAC also resulted in an increase in cell size, including the attachment surface area (F=29.303, p<0.001, n=4), nuclear area (F=541.880, p<0.001, n=4), and cell volume (H=14.118, p=0.003, n=4). Moreover, RAC induced the expression of p21 (F=6.457, p=0.008, n=4) and the activity of senescence-associated
-galactosidase (F=496.935, p<0.001, n=4), suggesting that kidney fibroblasts exposed to RAC acquire a senescent phenotype. Inhibition of p21 reduced cellular senescence (senescence-associated
-galactosidase: F=112.567, p<0.001, n=4), hypertrophy (attachment surface area: F=134.557, p<0.001, n=4), and myofibroblast transformation (
-SMA: F=34.633, p=0.004, n=4) induced by RAC. Interestingly, following RAC, kidney fibroblasts were arrested at the G2/M phase (interaction between cisplatin and cell cycle: F=49.164, p<0.001, n=5). Repeated treatment with paclitaxel, which is known to induce G2/M arrest (interaction between paclitaxel and cell cycle: F=99.768, p<0.001, n=4), upregulated -SMA (F=7.293, p=0.036, n=4) and fibronectin (F=11.762, p=0.014, n=4) in kidney fibroblasts. In summary, these findings suggest that RAC induces the transformation of kidney fibroblasts into myofibroblasts through G2/M arrest and cellular senescence.