Mitochondrial DNA and its respiratory chain products are defective in doxorubicin nephrosis.
BACKGROUND
Doxorubicin induces a self-perpetuating nephropathy characterized by early glomerular and late-onset tubular lesions in rats. We investigated the potential role of mitochondrial injury in the onset of these lesions.


METHODS
Rats were treated with intravenous doxorubicin (1 mg kg(-1) week(-1)) for 7 weeks and were sacrificed either 1 week ('short-term') or 30 weeks ('long-term') following the last dose. Additional rats received a single dose either 6 days or 2 h prior to euthanasia. All rats were killed at 48 weeks of age. Glomerular and tubular injury was monitored and correlated to the activity or expression of respiratory chain components. Finally, we quantified both nuclear and mitochondrial DNA (mtDNA) as well as superoxide production and the 4834 base pair 'common' mtDNA deletion.


RESULTS
The 'long-term' group had significant glomerular and tubular lesions, depressed activities of mtDNA-encoded NADH dehydrogenase and cytochrome-c oxidase (COX) and increased citrate synthase activity. In addition, expression of the mtDNA-encoded COX subunit I was reduced and mtDNA levels were decreased. In 'short-term' rats, there were fewer tubular lesions, but similar numbers of glomerular lesions activity. Among all animals, glomerular and tubular injury were inversely correlated with mtDNA levels, mtDNA-encoded respiratory chain activities and with the expression of the mtDNA-encoded respiratory chain subunit COX-I. Injury was positively correlated with superoxide production and the activities of nucleus-encoded mitochondrial or cytoplasmic enzymes. Kidneys from the 'long-term' group showed more mtDNA deletions than in 'short-term' animals and these were not observed in the other groups.


CONCLUSIONS
These results suggest an important role for quantitative and qualitative mtDNA alterations through the reduction of mtDNA-encoded respiratory chain function and induction of superoxide in doxorubicin-induced renal lesions.
Lebrecht
Dirk
D
Department of Rheumatology and Clinical Immunology, Albert-Ludwigs University, Freiburg, Germany.
Setzer
Bernhard
B
Rohrbach
Rolf
R
Walker
Ulrich A
UA
D000818:Animals; D001707:Biopsy, Needle; D030401:Cytochrome-c Oxidase Deficiency / Q000150:complications / Q000378:metabolism*; D004249:DNA Damage; D004272:DNA, Mitochondrial; D004195:Disease Models, Animal; D004317:Doxorubicin; D004579:Electron Transport; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000201:enzymology / Q000473:pathology; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000150:complications / Q000201:enzymology* / Q000473:pathology*; D011336:Probability; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000032:analysis / Q000378:metabolism; D012016:Reference Values; D013481:Superoxides / Q000032:analysis / Q000378:metabolism*
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D013481:Superoxides; D004317:Doxorubicin