Cadmium exposure enhances organic cation transporter 2 trafficking to the kidney membrane and exacerbates cisplatin nephrotoxicity

Abstract

Renal accumulation and exposure of cadmium originating from pollution in agricultural land and the prevalence of cigarette smoking remains an unneglectable human health concern. Whereas cadmium exposure has been correlated with increased incidence of a variety of kidney diseases, little is known pertaining to its effect on renal drug disposition and response in patients. Here, we report that cadmium exposure significantly increased the activity of organic cation transporter 2 (OCT2), a critical renal drug transporter recommended in United States Federal Drug Administration guidance for assessment during drug development. Cadmium enhanced OCT2 trafficking to the cell membrane both in vitro and in vivo. Mechanistically cadmium-mediated OCT2 translocation was found to involve protein-protein interaction between serine/ threonine-protein kinase AKT2, calcium/calmodulin and the AKT substrate AS160 in in vitro cellular studies. The formed protein complex could selectively facilitate phosphorylation of AKT2 at T309, which induced translocation of OCT2 to the plasma membrane. Moreover, cadmium exposure markedly exacerbated nephrotoxicity induced by cisplatin, an OCT2 substrate, by increasing its accumulation in the mouse kidney. Consistently, there was a significant correlation between plasma cadmium level and alteration of renal function in cervical cancer patients who underwent chemotherapy with cisplatin. Thus, our studies suggest that membrane transporter distribution induced by cadmium exposure is a previously unrecognized factor for the broad variation in renal drug disposition and response.

Divergent Regulation of OCT and MATE Drug Transporters by Cadmium Exposure

“…In this study, we firstly confirmed that Cd 2+ exposure led to an increased activity of OCTs as reported recently [ 18 ], while possessing an inhibitory effect on MATEs in HEK293 cells. Then, the mechanism underlying these divergent effects of Cd 2+ exposure on transporter activities was explored.…”

“…The uptake was performed in Krebs-Ringer HEPES (KRH) buffer for OCTs and in K + -based buffer (KBB) for MATEs as previously described [ 11 , 23 ]. As described previously [ 18 ], when applicable, the cells were pre-incubated with Cd 2+ for 20 min to enhance the activities of transporters, if any. Then, the uptake assay was performed in the presence or absence of Cd 2+ .…”

“…The presence of Cd 2+ in the uptake assays allowed us to examine whether there was any inhibitory effect of Cd 2+ on transporter activity. The toxicity of Cd 2+ exposure on HEK cells has been characterized in our previously work [ 18 , 23 ]. A pre-incubation of 20 min and uptake of 20 sec of Cd 2+ with the concentrations used in the present study did not influence cell viability.…”

“…Protein kinase A (PKA), protein kinase C (PKC), Yes1 kinase, phosphatidylinositol 3-kinase (PI3K)- and calmodulin-dependent kinases have been reported to regulate the function of OCT2 at the post-translational level [ 13 , 14 , 15 , 16 , 17 ]. Recently, we have demonstrated that OCT2 membrane translocation involves protein–protein interaction between serine/threonine-protein kinase AKT2, calcium/calmodulin, and the AKT substrate AS160 [ 18 ]. However, the detailed molecular mechanism remains to be depicted, and the regulation has yet to be verified in vivo.…”

“…Previously, the heavy metal cadmium (Cd 2+ ) has been reported to be a substrate of OCTs [ 21 , 22 ]. We have also demonstrated Cd 2+ as a substrate of MATEs [ 23 , 24 ], and the ion can increase the activity of OCT2 recently [ 18 ]. Although it has no physiological benefit, Cd 2+ exposure can alter multiple molecular signaling pathways [ 25 ], some of which have been indicated in regulation of OCTs and MATEs as described above.…”