Impairment by cyclosporine of membrane-mediated functions in kidney mitochondria.
This study was performed to evaluate whether cyclosporine penetrates kidney mitochondria and impairs mitochondrial functions, causing nephrotoxicity. Exposure of rat kidney cortical mitochondria in vitro to cyclosporine had little effect on the oxidation of glutamate plus malate. Oxidation of succinate was markedly inhibited by a toxic level of cyclosporine (25 to 50 nmol/mg protein) under resting (State 4) and ADP-stimulated (State 3) conditions. Under uncoupling conditions, induced by the proton ionophore, CCCP or by the calcium ionophore, A23187 plus calcium, mitochondrial respiration was unchanged by cyclosporine. In mitochondria isolated from rats treated with an immunosuppressive dose of cyclosporine (25 mg/kg/day, p.o.), respiration was not significantly impaired. The respiration stimulated by ADP was only diminished in mitochondria from rats treated with 75 mg/kg. The rate of calcium uptake was unchanged by cyclosporine under in vitro and in vivo conditions. Kidney mitochondria of untreated rats maintained in a medium containing respiratory substrates and phosphate released spontaneously accumulated calcium that was accompanied by large amplitude swelling and enhanced respiration. Cyclosporine in vitro inhibited the process of spontaneous calcium discharge at the concentration range of 0.1 to 0.5 nmol/mg protein. Swelling and respiration induced by accumulated calcium was significantly diminished in kidney mitochondria isolated from cyclosporine-treated rats given doses of 25 or 75 mg/kg. The data obtained indicate that cyclosporine interacts with the membrane of kidney mitochondria in virtually the same way under in vitro and in vivo conditions. Cyclosporine at an immunosuppressive level impairs calcium-induced membrane permeability and at a toxic level, the rate of ADP phosphorylation.
Strzelecki
T
T
Division of Urology and Transplantation Surgery, University of Massachusetts Medical School, Worcester.
Kumar
S
S
Khauli
R
R
Menon
M
M
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D003524:Cyclosporins / Q000633:toxicity*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D008933:Mitochondrial Swelling / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D015220:Calcium Channels; D003524:Cyclosporins