Abstract
Nephrotoxicity severely limits the chemotherapeutic efficacy of cisplatin (CDDP). Oxidative stress is associated with CDDP-induced acute kidney injury (AKI). Methylglyoxal (MG) forms advanced glycation end products that elevate oxidative stress. We aimed to explore the role of MG and its metabolite D-lactate and identify the proteins involved in CDDP-induced AKI. Six-week-old female BALB/c mice were intraperitoneally administered CDDP (5 mg/kg/day) for 3 or 5 days. Blood urea nitrogen (42.6 ± 7.4 vs. 18.3 ± 2.5; p < 0.05) and urinary N-acetyl-β-D-glucosaminide (NAG; 4.89 ± 0.61 vs. 2.43 ± 0.31 U/L; p < 0.05) were significantly elevated in the CDDP 5-day group compared to control mice. Histological analysis confirmed AKI was successfully induced. Confocal microscopy revealed TNF-α was significantly increased in the CDDP 5-day group. Fluorogenic derivatized liquid chromatography-tandem mass spectrometry (FD-LC-MS/MS) showed the kidney MG (36.25 ± 1.68 vs. 18.95 ± 2.24 mg/g protein, p < 0.05) and D-lactate (1.78 ± 0.29 vs. 1.12 ± 0.06 mol/g protein, p < 0.05) contents were significantly higher in the CDDP 5-day group than control group. FD-LC-MS/MS proteomics identified 33 and nine altered peaks in the CDDP 3-day group and CDDP 5-day group (vs. control group); of the 35 proteins identified using the MOSCOT database, 11 were antioxidant-related. Western blotting confirmed that superoxide dismutase 1 (SOD-1) and parkinson disease protein 7 (DJ-1) are upregulated and may participate with MG in CDDP-induced AKI. This study demonstrates TNF-α, MG, SOD-1 and DJ-1 play crucial roles in CDDP-induced AKI.
Highlights
Cisplatin is widely used as a chemotherapeutic agent for a variety of cancers
blood urea nitrogen (BUN) was significantly higher at day 5 and NAG was significantly higher at days 3 and 5 in the CDDP group compared to the control group
The tubulointerstitial histological score (TIHS) of the periodic acid-Schiff (PAS)-stained tissues confirmed that CDDP-induced pathological changes were observed in both the CDDP 3-day group and CDDP 5-day group
Summary
Cisplatin (cis-diamminedichloroplatinum II; CDDP) is widely used as a chemotherapeutic agent for a variety of cancers. One-third of patients treated with CDDP develop nephrotoxicity, which limits the application of this drug [1, 2]. CDDP-induced nephrotoxicity is associated with damage to the S1 and S3 segments of the proximal tubules. High concentrations of CDDP induce necrosis of the kidney tissues, whereas lower concentrations can promote apoptosis in human kidney cells [3]. CDDP causes reactive oxygen species (ROS)-induced oxidative stress and lipid peroxidation, which result in membrane dysfunction and production of toxic metabolites. A relationship between tumor necrosis factor-α (TNF-α) and CDDP-induced nephrotoxicity was previously described [4,5,6,7]
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