Cisplatin-Induced Kidney Toxicity: Potential Roles of Major NAD+-Dependent Enzymes and Plant-Derived Natural Products

Abstract

Cisplatin is an FDA approved anti-cancer drug that is widely used for the treatment of a variety of solid tumors. However, the severe adverse effects of cisplatin, particularly kidney toxicity, restrict its clinical and medication applications. The major mechanisms of cisplatin-induced renal toxicity involve oxidative stress, inflammation, and renal fibrosis, which are covered in this short review. In particular, we review the underlying mechanisms of cisplatin kidney injury in the context of NAD⁺-dependent redox enzymes including mitochondrial complex I, NAD kinase, CD38, sirtuins, poly-ADP ribosylase polymerase, and nicotinamide nucleotide transhydrogenase (NNT) and their potential contributing roles in the amelioration of cisplatin-induced kidney injury conferred by natural products derived from plants. We also cover general procedures used to create animal models of cisplatin-induced kidney injury involving mice and rats. We highlight the fact that more studies will be needed to dissect the role of each NAD⁺-dependent redox enzyme and its involvement in modulating cisplatin-induced kidney injury, in conjunction with intensive research in NAD⁺ redox biology and the protective effects of natural products against cisplatin-induced kidney injury.

Keywords: cisplatin; kidney toxicity; mitochondria; natural products; oxidative stress; redox imbalance.

Figure 1

Diagram showing the proximal convoluted tubule (PCT) as the major site of cisplatin accumulation and toxicity in the nephrons.

Figure 2

Major pathological mechanisms of cisplatin-induced kidney injury. Cisplatin enters into cell via copper transporter 1 (Ctr1) or organic anion transporter 2 (OCT2) receptors on the cell surface. Once inside the cell, cisplatin can go on to elicit a variety of actions or cellular responses such as nuclear and mitochondrial DNA damage, perturbation of mitochondrial function that can elevate ROS production, and decrease in NAD content and decrease in activity of NAD-dependent enzymes such as sirtuins. DNA damage could activate PARP, which consumes NAD, and in turn could further lower the NAD content, leading to NAD redox imbalance. Cisplatin can also activate inflammation-signaling pathways such as NF-kB activation via MAPKs. These events can result in interstitial fibrosis and eventual kidney failure.

Figure 3

Outlines of rodent models used for studying cisplatin-induced kidney injury. Shown are the dose ranges for either mice or rats involving either AKI or CKD. It should be noted that these are just general guidelines for designing an experiment and should be modified for specific experimental objectives if needed.

Figure 4

Major NAD-dependent redox enzymes that are potentially involved in cisplatin-induced kidney toxicity.

Figure 5

Schematic diagram depicting the protective mechanisms of natural products against cisplatin-induced kidney toxicity listed in Table 1.