Cadmium-induced nephrotoxicity in rhesus monkeys (Macaca mulatta) in relation to protein calorie malnutrition.
In this study, we compared results obtained in protein calorie malnourished (PCM) monkeys and controls given Cd2+ (5 mg Cd2+/kg body wt./day) orally for 24 weeks. After 16 weeks of Cd2+ exposure, an indolent renal failure develops in PCM monkeys which resulted in significant increase in urinary excretion of total protein, Cd2+, Zn2+ and Ca2+ as compared to corresponding to Cd(2+)-treated control group. In isolated proximal tubule brush border membrane vesicles (BBMV), Cd2+, Zn2+ and Ca2+ transport were significantly impaired in Cd(2+)-exposed PCM monkeys as compared to Cd(2+)-treated controls. The mechanism of higher urinary excretion of Cd2+, Zn2+ and Ca2+ was examined by analyzing the kinetic parameters of transport systems. The kinetic studies of Cd2+, Zn2+ and Ca2+ transport systems in the BBMV preparations of Cd(2+)-exposed PCM monkeys exhibited a significant decrease in Vmax and an appreciable increase in Km as compared to Cd(2+)-treated controls. These findings suggested that Cd2+ treatment of PCM monkeys caused either a decrease in the number of transporters in the brush border membrane or an increase in the number of less active transporters for Cd2+, Zn2+ and Ca2+. Furthermore, brush border membrane-bound enzymes, viz. alkaline phosphatase and leucine aminopeptidase, activities were significantly impaired in Cd(2+)-exposed PCM monkeys. Cadmium content in kidney cortex of Cd(2+)-exposed PCM monkeys was 3.34-fold higher than Cd(2+)-exposed controls. These findings also established that Cd2+ not bound to metallothionein (MT) was significantly higher in Cd-exposed PCM monkeys, which may be an important determinant in renal toxicity by interacting with sensitive sites in the renal cells and causing renal damage in Cd-exposed PCM monkeys.
Prasad
R
R
Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
Nath
R
R
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002104:Cadmium / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity* / Q000652:urine; D002118:Calcium / Q000097:blood / Q000652:urine; D018753:Diet, Protein-Restricted; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D007931:Leucyl Aminopeptidase / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D008871:Microvilli / Q000187:drug effects / Q000201:enzymology; D011502:Protein-Energy Malnutrition / Q000378:metabolism*; D011507:Proteinuria / Q000139:chemically induced; D051437:Renal Insufficiency / Q000139:chemically induced*; D015032:Zinc / Q000097:blood / Q000652:urine
D002104:Cadmium; D008668:Metallothionein; D000469:Alkaline Phosphatase; D007931:Leucyl Aminopeptidase; D015032:Zinc; D002118:Calcium