metallothionein and Kidney-Tubular-Necrosis--Acute

Rats injected with mercuric chloride develop an acute renal tubular necrosis with uremia, which is frequently lethal. Pretreatment for 3 or 7 days with a protein-free diet reduces the mortality, the clinical signs (tremor), and the severity of renal tubular necrosis, and ameliorates the uremic chemical findings in the serum. Similar results followed injection of a nephrotoxic amino acid, D-serine, after pretreatment with a protein-free diet. Indirect evidence suggests that induction of metallothionein may be involved, at least in the experiments with mercury. Acute uremia produced by nephrotoxic chemicals may be useful for further studies of the role of nutrition in uremia, while avoiding the surgical procedures and prolonged observations required for the "remnant kidney" models.

Topics: Acute Disease; Animals; Biomarkers; Body Weight; Diet, Protein-Restricted; Disease Models, Animal; Dose-Response Relationship, Drug; Injections, Subcutaneous; Kidney; Kidney Tubular Necrosis, Acute; Male; Mercuric Chloride; Metallothionein; Phosphates; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sucrose; Time Factors; Treatment Outcome; Urea; Uremia

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.

Topics: Acute Kidney Injury; Animals; DNA; Free Radicals; Gentamicins; Hydroxyl Radical; In Vitro Techniques; Kidney; Kidney Cortex; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Male; Metallothionein; Rats; Rats, Wistar; Reactive Oxygen Species; Sodium-Potassium-Exchanging ATPase; Zinc

Wistar rats were treated with gentamicin in single (80 mg/kg) or repeated doses (7 x 40 mg/kg) subcutaneously. Total protein as well as excretion of essential metals (Cu, Zn) with the urine were determined 24 hr after 1, 3 and 7 dosages as well as 3 and 7 days after the termination of administration. At the same time kidneys were examined histopathologically by light microscopy. Simultaneously, Cu, Zn and metallothionein levels in kidneys and liver were determined. Rats receiving gentamicin demonstrated progressive renal proximal tubular necrosis at the end of 7 days administration. At the same time elevated copper and zinc levels were observed in urine. These essential metals seem to be an indicator of gentamicin nephrotoxicity.

Topics: Animals; Copper; Female; Gentamicins; Kidney; Kidney Tubular Necrosis, Acute; Kidney Tubules, Proximal; Metallothionein; Proteinuria; Rats; Rats, Wistar; Zinc

Wistar rats were used to study the protective effect of zinc-induced metallothionein (MT) synthesis on gentamicin nephrotoxicity. We found that s.c. pre-injection of ZnSO4 (Zn 10 mg/kg/day) for 5 days could ameliorate proximal tubular necrosis and acute renal failure caused by an 8-day s.c. injection of gentamicin (100 mg/kg/day), while preinjection of saline instead of zinc or zinc and gentamicin together could not. In the zinc-pretreated rats (n = 6), renal cortical metallothionein level was significantly higher than that of normal (n = 8, p less than 0.001) and the saline controls (n = 6, p less than 0.001). Since MT is a scavenger of hydroxyl radical, it is proposed that hydroxyl radical plays a role in the pathogenesis of gentamicin nephrotoxicity and that preinjection of zinc could ameliorate gentamicin nephrotoxicity via the induction of renal cortical MT synthesis.

Topics: Acute Kidney Injury; Animals; Free Radical Scavengers; Gentamicins; Hydroxides; Hydroxyl Radical; Kidney Cortex; Kidney Tubular Necrosis, Acute; Male; Malondialdehyde; Metallothionein; Rats; Rats, Inbred Strains; Sulfates; Superoxide Dismutase; Zinc; Zinc Sulfate

It has previously been reported that cadmium (Cd) induces renal lesions only after sequestration by endogenous metallothionein (MT), and not in the form of simple salts. However, in this report we detail findings of acute CdCl2-induced renal lesions in the Syrian hamster, which appear to be species specific as neither rats nor mice showed such lesions. Adult rats and mice of different strains and Syrian hamsters (Cr:RGH) were given Cd doses ranging from 30-50 mumol/kg, sc, and examined histologically for renal lesions between 2 hr and 7 days later. Hamsters developed necrosis of the proximal renal tubules 12-24 hr after CdCl2 treatment at an average incidence of 60% in both sexes. Tubular regeneration occurred within 1 week as shown by immunocytochemical localization of DNA synthesis with 5-bromo-2'-deoxyuridine. By electron microscopy, initial changes with Cd (16 hr) included cytoplasmic vesiculation and dilatation of endoplasmic reticulum, and swelling of mitochondria followed rapidly by enlargement of vacuoles, nuclear changes, and cellular disintegration. Rats and mice showed no such lesions even at lethal doses of Cd (40-50 mumol/kg). At maximum tolerated doses of Cd (approximately LD 10: for rats and mice, 35 mumol/kg; for hamsters, 50 mumol/kg) renal Cd content was not higher in hamsters than in the other species 24 hr after injection; hamsters, in fact, had the lowest Cd content. Likewise, basal or Cd-induced levels of renal MT were not remarkably different between these species. These results indicate the hamster is uniquely susceptible to acute effects of Cd on the kidney and that this effect is not related to an unusually high concentration of CdCl2 or unusually low basal or induced levels of MT in the kidney.

Topics: Animals; Cadmium; Cadmium Chloride; Cricetinae; Kidney; Kidney Diseases; Kidney Tubular Necrosis, Acute; Mesocricetus; Metallothionein; Mice; Mice, Inbred Strains; Microscopy, Electron; Rats; Rats, Inbred F344

Concentrations of metallothionein and metals, i.e. cadmium, copper and zinc, were determined in six rejected transplanted human kidneys and one kidney prepared for transplantation. Tissue samples separated by gel chromatography showed that almost all of cadmium in tissue was in the form of firmly bound cadmium-metallothionein.

Topics: Adult; Aged; Cadmium; Graft Rejection; Humans; In Vitro Techniques; Kidney; Kidney Transplantation; Kidney Tubular Necrosis, Acute; Metallothionein; Middle Aged; Organ Preservation

The extensive renal tubular necrosis that results in male rats after the intravenous injection of a single, low dose of equine kidney cadmium (Cd), zinc(Zn)-metallothionein (MT) (0.2 mg MT-bound-Cd/kg body wt.) is followed within 72 h by active regeneration. With repeated administration of the same dose at 3- or 4-day intervals, lesion resolves although, at least initially, the kidney content of Cd increases progressively. At any time during treatment, about 40% of the accumulated Cd is bound as the endogenous (Cd, Cu)MT. The rate of increase in the renal Cd content is dependent on the ratio of Cd:Zn in the injected metalloprotein, and is appreciably less when the constant dose of protein-bound Cd is given as a (2.4 Cd:1 Zn)MT, than as a (3.0 Cd:1 Zn)MT. On repeated administration of the latter preparation, however, the concentration of Cd in the kidney does not attain a critical concentration, above which persistent tubular damage occurs, but reaches a maximum of about 150-160 micrograms Cd/g wet wt. (after 16 doses) and then declines. After 19 doses of the (2.4 Cd:1 Zn)MT under the same conditions, the renal Cd concentration is submaximal and is less (92 micrograms Cd/g wet wt.) than that after either 16 or 27 doses of the (3.0 Cd:1 Zn)MT. In animals that are dosed with either of the heterologous MT preparations, the first dose, although not innocuous, seems to protect the kidneys against further damage by subsequent doses. Repeated doses, however, lead to vascular changes, e.g. lymphoid infiltration, periarteriole oedema and dilation of the arcuate veins, and to dilation of the glomerular spaces.

Topics: Animals; Cadmium; Horses; Kidney; Kidney Tubular Necrosis, Acute; Liver; Male; Metallothionein; Rats; Rats, Inbred Strains; Regeneration