Magnesium attenuates cisplatin-induced nephrotoxicity by regulating the expression of renal transporters

Cisplatin (CDDP)-induced nephrotoxicity (CIN) is one of the most serious toxicities caused by this potent antitumor agent. It has been reported that Mg premedication attenuates CIN in clinical trials; however, the mechanism underlying its nephroprotection is not fully understood. Therefore, the aim of this study was to determine whether Mg administration affects CDDP accumulation by regulating the expression level of renal transporters. Rats were divided into control, Mg (40mg/kg) alone, 2.5mg/kg CDDP with (20 and 40mg/kg) and without Mg, 5mg/kg CDDP groups. These substances were administered on the same day and 7 days later their kidneys were removed. The expression levels of renal transporters and platinum (Pt) accumulation were analyzed. The serum creatinine level was significantly increased by CDDP administration and treatment with Mg significantly ameliorated such elevation. The expressions of the renal organic cation transporter 2 (rOct2) and renal multidrug and toxin extrusion protein 1 (rMate1) were downregulated and upregulated, respectively following co-administration with Mg, which significantly reduced the renal Pt accumulation in the 2.5mg/kg CDDP-treated group. Moreover, Mg dose-dependently downregulated rOct2, not affecting rMate expression, resulting in the attenuation of CIN. Mg co-administration protected the downregulation of the transient receptor potential subfamily Melastatin 6 (rTrpm6), but not the epidermal growth factor (rEgf), as a result, Mg co-injection attenuated CDDP-induced hypomagnesemia. In conclusion, Mg co-administration reduced Pt accumulation by regulating the expression of the renal transporters, rOct2 and rMate1 and, thereby, attenuated CIN.