Mechanism of Aminonucleoside-Induced Nephrosis in the Rat. III. Kidney Mitochondrial Phosphorylation and Dephosphorylation Activity. ∗

Abstract

Summary

Results of time-course studies of the development of a significant reduction in disappearance of inorganic phosphate, associated with oxidation of succinate in kidney mitochondria of aminonucleoside-nephrotic rats, clearly indicate the establishment of this effect as early as the 4th day during the induction of the nephrotic syndrome, and prior to onset and development of massive proteinuria. Oxygen uptake was not similarly altered until the 6th day of aminonucleoside administration and occurred in parallel with onset of proteinuria. Under experimental conditions closely resembling those employed in the oxidative phosphorylation studies, no significant differences were noted in dephosphorylation of ADP, ATP, and G-6-P by kidney mitochondria of either normal or aminonucleoside-nephrotic rats. These findings, and the additional observation of aminonucleoside-inhibition of kidney mitochondrial ATPase activity, appear to justify the conclusion that induction of aminonucleoside-nephrosis in the rat results in impaired kidney mitochondrial phosphorylation. Failure of aminonucleoside, added in vitro to normal rat kidney mitochondria, to significantly alter phosphorylation suggests that this effect is of secondary origin. Demonstration of inhibited phosphorylation when aminonucleoside is added in vitro to normal rat kidney submitochondrial phosphorylating complexes, however, suggests a primary effect. It is suggested that the mechanism of action of aminonucleoside may be bimodal, producing some of its metabolic effects either directly or indirectly through inhibition of reactions producing energy-rich ATP and some directly through inhibition of reactions by which the energy of ATP is released.