Comparison Of Nephrotoxicity Induced By Gentamicin And Etimicin And Prevention Of Trimetazidine Against Gentamicin-induced Nephrotoxicity

Gentamicin mainly constitutes by C1、C1a、C2, which is one of the aminoglycosides. Etimicin, a derivative of gentamicin C1a, belongs to aminoglycosides. It was reported that nephrotoxicity induced by etimicin was lower than that induced by gentamicin from the angle of the biochemical indicators and pathological morphologic changes. This study aims to compare the nephrotoxicity induced by etimicin with that induced by gentamicin from the angle of apoptosis and pathological morphologic changes.The animals were randomLy divided into three groups:etimicin group, gentamicin group and vehicle group with5animals in each group. Rats in etimicin group and gentamicin group were intraperitoneally injected with etimicin sulfate and gentamicin sulfate respectively in a daily dose of100mg·kg-1for five days, while rats in vehicle group were intraperitoneally injected physiological saline. All animals were sacrificed24h after the last dosing and both kidneys of each rat were harvested. The concentrations of etimicin and gentamicin were detected with HPLC and fluorescence polarization immunoassay (FPIA) method, respectively. The apoptosis of renal tubular epithelial cells was examined by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) method. Morphologic changes of kidney were determined by hematoxylin-eosin staining (HE).The results showed that the concentrations of etimicin and gentamicin in the renal cortex were (463.4±120.2)μg·g-1and (487.86±97.3)μg·g-1, respectively, which had no significant differences (P>0.05). The number of apoptotic renal tubular epithelial cells of the etimicin group and gentamicin group were (820.84±242.99) n·mm-2,(1112.04±353.05) n· mm-2, respectively. The numbers of apoptotic cells of the etimicin group was reduced by26.20%of these of gentamicin group, but there was no significant difference (P>0.05) between the two groups due to bigger standard deviate. The degree of pathological morphologic change in the etimicin group was slighter than that in the gentamicin group. Those results suggested that the degree of nephrotoxicity induced by etimicin is slighter than that induced by gentamicin.Except controlling daily does, there was no effective way to prevent nephrotoxicity of aminoglycoside drugs such as gentamicin and Etimicin in clinic. There was only one study reported that trimetazidine could protected the rats against gentamicin-induced nephrotoxicity. But the mechanism of action is not known. This study aims to evaluate the effect of trimetazidine on GM-induced nephrotoxicity in rats from the angle of accumulation of GM in the renal cortex, the apoptosis of renal epithelial cells and pathological morphologic changes.The rats were divided into six groups (n=4):(A) Vehicle control group;(B)TMZ5mg·kg-1·d-1group;(C) TMZ10mg·kg-1·d-1group;(D)GM group;(E) TMZ5mg·kg-1·d-1+GM group;(F) TMZ10mg·kg-1·d-1+GM group. Trimetazidine was pretreated for2days by intragastric administration. From the third day, gentamicin was given by intraperitoneal injection after the intragastric administration. Trimetazidine was given once a day for7continuous days; gentamicin was given once a day for5days. Rats in vehicle control group were treated with physiological saline by the same route of administration as above.24hours after the last dosing, animals were sacrificed and both kidneys of each rat were harvested. The concentrations of gentamicin in kidney were detected with FPIA. The apoptotic renal tubular epithelial cells were examined by TUNEL method. Morphologic changes of kidney was determined by hematoxylin-eosin staining (HE). The results showed that the concentrations of gentamicin in kidney of groups of TMZ10mg·kg-1·d-1+GM, TMZ5mg·kg-1·d-1+GM and GM alone were (258.90±84.07) ug·g-1tissue,(340.95±102.09) μg·g-1tissue,(511.78±112.73)μg·g-1tissue, respectively. There was a significant difference between groups of TMZ10mg·kg-1·d-1+GM and GM alone (P<0.05). The numbers of apoptotic renal tubular epithelial cells of above groups were (153.97±47.83) n·mm-2,(301.15±96.10) n·mm-2,(497.57±102.75) n·mm-2, respectively. The former two groups had significant difference as compared with the latter group (P<0.05).The results suggested that trimetazidine can protect the rat against gentamicin-induced nephrotoxicity by decreasing the accumulation of gentamicin in kidney.