Mechanism of gentamicin nephrotoxicity in rats and the protective effect of zinc-induced metallothionein synthesis.
We examined the role of reactive oxygen metabolites and the protective effect of zinc-induced metallothionein (MT) synthesis on gentamicin nephrotoxicity both in vivo and in vitro. In vivo study we found that the MT content of renal cortex of the zinc preinjected rats was significantly increased, and proximal tubular necrosis and acute renal failure caused by injection of gentamicin were ameliorated. In suspended proximal tubules (PT), Na(+)-K(+)-ATPase activity and DNA synthesis were suppressed by the addition of gentamicin, but in zinc-pretreated rats' PT, these were not suppressed by the addition of gentamicin. Meanwhile MDA and hydroxyl radicals were significantly less in zinc-pretreated rats' PT compared to that in the control. Finally, we found that gentamicin enhanced superoxide anion and hydroxyl radical productin in renal cortical mitochondria. Superoxide anion could be suppressed by SOD and hydroxyl radical could be scavenged by DMSO, DFO and CAT. Our data confirm that hydroxyl radicals play a role in the pathogenesis of gentamicin nephrotoxicity, gentamicin can induce suppression of Na(+)-K(+)-ATPase activity and DNA synthesis in rats' proximal tubules leading to renal injury; this injury may be relevant to reactive oxygen metabolites generated by gentamicin. Renal cortical mitochondria is the source of reactive oxygen metabolites, which induces renal injury, and zinc-induced metallothionein synthesis could ameliorate gentamicin nephrotoxicity via scavenging reactive oxygen metabolites.
Du
X H
XH
Department of Nephrology, China-Japan Friendship Hospital, Beijing.
Yang
C L
CL
D058186:Acute Kidney Injury / Q000139:chemically induced / Q000517:prevention & control; D000818:Animals; D004247:DNA / Q000096:biosynthesis; D005609:Free Radicals; D005839:Gentamicins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D017665:Hydroxyl Radical / Q000378:metabolism; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000517:prevention & control; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008668:Metallothionein / Q000096:biosynthesis*; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D015032:Zinc / Q000494:pharmacology*
D005609:Free Radicals; D005839:Gentamicins; D017382:Reactive Oxygen Species; D017665:Hydroxyl Radical; D004247:DNA; D008668:Metallothionein; D000254:Sodium-Potassium-Exchanging ATPase; D015032:Zinc