title: Calcium supplementation and thyroid hormone protect against gentamicin-induced inhibition of proximal tubular Na+,K(+)-ATPase activity and other renal functional changes.
abstract: Gentamicin can cause proximal tubule necrosis. We have shown that inhibition of PT Na+,K(+)-ATPase activity is rapidly induced by gentamicin. We have now investigated whether manipulations known to attenuate the negative effects of gentamicin on renal excretory capacity, i.e. high calcium intake and L-thyroxine treatment, will also attenuate gentamicin-induced inhibition of Na+,K(+)-ATPase activity and ameliorated signs of proximal tubule damage. Rats were gentamicin- or vehicle-treated for 7 days. Sub-groups were given 4% calcium (Ca) supplements or L-thyroxine 20 micrograms 100 g-1 body weight daily. Gentamicin significantly reduced the glomerular filtration rate and increased the urinary excretion of the proximal tubule lysosomal enzyme, N-acetyl-beta-D-glucosaminidase. Gentamicin significantly reduced proximal tubule Na+,K(+)-ATPase activity, measured in single permeabilized proximal tubule segments. Sodium excretion was inversely correlated to proximal tubule Na+,K(+)-ATPase activity. Both calcium and L-thyroxine alleviated all gentamicin-induced side-effects on renal function as well as on proximal tubule Na+,K(+)-ATPase activity. Calcium and L-thyroxine had no significant effect on renal function. L-thyroxine, but not calcium, increased proximal tubule Na+,K(+)-ATPase activity in control rats. Renal cortical tissue gentamicin concentration was not influenced by calcium but was significantly lowered by L-thyroxine. Two procedures which, via different mechanisms, afford protection from gentamicin-induced changes in renal function also give protection from gentamicin-induced inhibition of Na+,K(+)-ATPase activity. This suggests that loss of integrity of the Na+,K(+)-ATPase enzyme contributes to gentamicin-induced nephrotoxicity.
authors.affiliation: Department of Pediatrics, Karolinska Institutet, Sweden.
authors.forename: Y
authors.initials: Y
authors.lastname: Fukuda
authors.forename: A C
authors.initials: AC
authors.lastname: Eklöf
authors.forename: A S
authors.initials: AS
authors.lastname: Malmborg
authors.forename: A
authors.initials: A
authors.lastname: Aperia
mesh_terms: D000118:Acetylglucosaminidase / Q000652:urine; D000818:Animals; D002118:Calcium / Q000008:administration & dosage* / Q000494:pharmacology; D005839:Gentamicins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007683:Kidney Tubular Necrosis, Acute / Q000139:chemically induced / Q000517:prevention & control*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000652:urine; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013974:Thyroxine / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D005839:Gentamicins; D012964:Sodium; D000118:Acetylglucosaminidase; D000254:Sodium-Potassium-Exchanging ATPase; D013974:Thyroxine; D002118:Calcium