Objective: Cisplatin is a widely used chemotherapeutic agent due to its ability to damage DNA in the treatment of cancer. However, its clinical application is often limited by adverse effects on normal tissues, especially the kidneys. Understanding the molecular mechanisms of cisplatin-induced nephrotoxicity is crucial for developing strategies to mitigate its side effects. In this study, we aimed to elucidate the molecular mechanisms underlying cisplatin-induced DNA damage and apoptosis in human renal epithelial cells, with a focus on key signaling pathways and mediators that drive nephrotoxicity. Methods: To explore these mechanisms, human proximal tubule epithelial cells (HK-2) were treated with cisplatin. The study assessed DNA damage response (DDR) and stress-related protein expression, cell cycle distribution, and apoptosis. Activation of mitogen-activated protein kinases (MAPKs), particularly Extracellular signal-regulated Kinase (ERK), was analyzed, along with the expression and functional role of activating transcription factor 3 (ATF3) and tumor protein p53 (p53). Results: Cisplatin treatment upregulated DDR and stress response proteins, induced S phase arrest, and increased the SubG1 population, indicating apoptotic cell death. ERK was identified as a critical mediator of cisplatin-induced DNA damage and stress responses. ATF3 expression was significantly elevated in an ERK-dependent manner and required p53 activation. Knockdown of ATF3 reduced cisplatin-induced DNA damage, highlighting its role in the cytotoxic response. Conclusions: Cisplatin induces nephrotoxicity through ERK- and p53-dependent upregulation of ATF3, which is associated with DNA damage and cell death, suggesting a modulatory role in the cellular stress response. These findings provide novel insights into the molecular basis of cisplatin-induced renal injury and suggest potential therapeutic targets to alleviate its adverse effects.
Lee et al. (Thu,) studied this question.