Cisplatin-Induced Nephrotoxicity and Kidney Injury Mechanisms

Cisplatin is a platinum-based chemotherapeutic agent widely employed against diverse solid tumours. Despite its efficacy, cisplatin exerts a dose-limiting toxicity on the kidney, manifesting as acute kidney injury (AKI) and, in some cases, progressing to chronic kidney disease (CKD). The primary locus of injury resides in the renal proximal tubules, where cisplatin accumulates and triggers a cascade of cellular stress responses. Key mechanisms include DNA damage and activation of p53-dependent apoptotic pathways, oxidative stress driven by reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and mitochondrial dysfunction. Emerging evidence implicates regulated cell death modalities—such as ferroptosis—alongside maladaptive repair programmes that involve proinflammatory and profibrotic signalling. Persistent activation of transcription factors and epigenetic regulators, including NF-κB, EZH2 and sirtuin 1, further propagates tubular epithelial cell senescence and matrix deposition, culminating in renal fibrosis. A detailed understanding of these intersecting pathways offers avenues for therapeutic intervention to preserve renal function in patients undergoing cisplatin chemotherapy.

Research from Nature Portfolio

Recent studies have illuminated the role of microRNAs in orchestrating metabolic and cell-death pathways during cisplatin-induced injury. High-resolution transcriptome mapping in murine kidneys revealed that specific cisplatin-induced microRNAs target messenger RNAs governing mitochondrial branched-chain amino acid catabolism, thereby promoting lipid peroxidation and ferroptosis in proximal tubular cells. Modulation of this microRNA–mRNA axis holds promise for attenuating oxidative lipid damage. In parallel, investigation of thrombomodulin (TM)—a multifunctional endothelial glycoprotein—demonstrated that post-injury administration of TM in a cisplatin-treated mouse model significantly reduced blood urea nitrogen and serum creatinine levels. TM suppressed ROS generation and caspase-3-mediated apoptosis in tubular epithelial cells, while also mitigating ER stress signalling. These findings position TM and microRNA modulators as candidate protectants against cisplatin nephrotoxicity.

Cisplatin-Induced Nephrotoxicity and Kidney Injury Mechanisms publication trend

The graph below shows the total number of articles in cisplatin-induced nephrotoxicity and kidney injury mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Nephrotoxicity: Kidney damage caused by toxic substances, often resulting in impaired filtration and tubular function.

Acute kidney injury (AKI): Rapid decline in renal function, typically within hours to days, leading to accumulation of metabolic waste.

MicroRNA (miRNA): Small non-coding RNA molecules that regulate gene expression by binding target messenger RNAs.

Reactive oxygen species (ROS): Chemically reactive molecules containing oxygen that can damage cellular components.

Endoplasmic reticulum (ER) stress: Cellular condition arising from accumulation of misfolded proteins in the ER lumen, triggering adaptive or apoptotic responses.

Ferroptosis: Regulated form of cell death driven by iron-dependent lipid peroxidation.

Cellular senescence: Stable arrest of cell proliferation accompanied by a proinflammatory secretory phenotype.

References

1. MicroRNA-mediated attenuation of branched-chain amino acid catabolism promotes ferroptosis in chronic kidney disease. Nature Communications (2023).
2. Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress. Scientific Reports (2024).
3. Tubular aryl hydratocarbon receptor upregulates EZH2 to promote cellular senescence in cisplatin-induced acute kidney injury. Cell Death & Disease (2023).
4. p53 in Proximal Tubules Mediates Chronic Kidney Problems after Cisplatin Treatment. Cells (2022).
5. p53/sirtuin 1/NF-κB Signaling Axis in Chronic Inflammation and Maladaptive Kidney Repair After Cisplatin Nephrotoxicity. Frontiers in Immunology (2022).