The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity

Abstract

The usefulness and efficacy of cisplatin, a chemotherapeutic drug, are limited by its toxicity to normal tissues and organs, including the kidneys. The uptake of cisplatin in renal tubular cells is high, leading to cisplatin accumulation and tubular cell injury and death, culminating in acute renal failure. While extensive investigations have been focused on the signaling pathways of cisplatin nephrotoxicity, much less is known about the mechanism of cisplatin uptake by renal cells and tissues. In this regard, evidence has been shown for the involvement of organic cation transporters (OCT), specifically OCT2. The copper transporter Ctr1 is highly expressed in the renal tubular cells; however, its role in cisplatin nephrotoxicity is not known. In this study, we demonstrate that Ctr1 is mainly expressed in both proximal and distal tubular cells in mouse kidneys. We further show that Ctr1 is mainly localized on the basolateral side of these cells, a proposed site for cisplatin uptake. Importantly, downregulation of Ctr1 by small interfering RNA or copper pretreatment results in decreased cisplatin uptake. Consistently, downregulation of Ctr1 suppresses cisplatin toxicity, including cell death by both apoptosis and necrosis. Cimetidine, a pharmacological inhibitor of OCT2, can also partially attenuate cisplatin uptake. Notably, cimetidine can further reduce cisplatin uptake and cisplatin toxicity in Ctr1-downregulated cells. The results have demonstrated the first evidence for a role of Ctr1 in cisplatin uptake and nephrotoxicity.

Inhibition of PKCδ reduces cisplatin-induced nephrotoxicity without blocking chemotherapeutic efficacy in mouse models of cancer

“…Renal tissues were collected and homogenized for cisplatin measurement using flameless atomic absorption spectrometry as previously described (69).…”

Protective effect of pomegranate seed oil against cisplatin-induced nephrotoxicity in rat

“…Tubular injury is recognized as a major pathogenic factor in cisplatin-induced nephrotoxicity. 4 Copper transporter receptor1 (Ctr1) and organic cation receptor2(Oct2) are involved in cisplatin transport in tubular cells. 1,4 Cisplatin causes impairment of kidney function and acute renal failure via several mechanisms including the inhibition of protein synthesis, generation of reactive oxygen species (ROS), mitochondrial dysfunction, DNA damage and apoptosis.…”

Protective effect of CV247 against cisplatin nephrotoxicity in rats

“…19 Copper transporter 1 (Ctr1) and the organic cation transporter 2 (OCT2) are critically involved in cisplatin uptake into renal tubular epithelial cells consequently determining nephrotoxicity [20][21][22][23] . Oxidative stress, induction of an inflammatory response and direct DNA damage are also implicated in the mechanisms of cisplatin-induced nephrotoxicity.…”