Nephropathy induced by cisplatin results from mitochondrial disruption, impaired energy metabolism, altered expression of renal transporters, and accumulation of urinary toxins

Background

The administration of platinum-based drugs such as cisplatin and its derivatives, which are frequently used during clinical chemotherapy, is highly restricted due to the incidence of nephrotoxicity. The present study focused on investigating cisplatin-induced nephrotoxicity from the perspective of energy metabolism, renal transporter expression and urinary toxin accumulation.

Methods

This study investigated cisplatin's toxic effects, including nephrotoxicity, cardiotoxicity, hepatotoxicity, pulmonary toxicity, and splenotoxicity. We used transmission electron microscopy (TEM) and scanning electron microscopy (SEM) to characterize the accumulation of cisplatin in the kidney and the structure of renal mitochondria. The production of reactive oxygen species (ROS) induced by cisplatin in renal tubular epithelial cells was evaluated by in vitro experiments, and apoptosis of renal tubular epithelial cells and alterations to the renal microvasculature were assessed. Metabolites associated with the glycolytic and tricarboxylic acid pathways were measured, and renal transporters expression, autophagy, and urinary toxins (UTs) accumulation were also assessed.

Results

Our results reveal that cisplatin-induced varying degrees of damage to the heart, liver, spleen, lungs, and kidneys, including inflammatory and fibrotic damage. Accumulation of cisplatin in renal mitochondria disrupted mitochondrial structure and mitochondrial function, as evidenced by decreased levels of glucose 6-phosphate and ribose 5-phosphate and elevated levels of isocitric acid. Cisplatin-induced accumulation of ROS in renal tubular epithelial cells led to apoptosis and, ultimately, constriction or loss of renal microvasculature. Furthermore, dysregulation of renal transporter expression, activation of autophagy and increased accumulation of UTs was observed.

Conclusion

Accumulation of cisplatin in the kidney led to damage to mitochondrial structure and function, apoptosis of renal tubular epithelial cells, constriction or loss of renal microvasculature, dysfunction of renal transporters, activation of autophagy, and accumulation of UTs.