Calcium supplementation and thyroid hormone protect against gentamicin-induced inhibition of proximal tubular Na+,K(+)-ATPase activity and other renal functional changes.

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.