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.
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.
Authors: Mei Tran; Denise Tam; Amit Bardia; Manoj Bhasin; Glenn C Rowe; Ajay Kher; Zsuzsanna K Zsengeller; M Reza Akhavan-Sharif; Eliyahu V Khankin; Magali Saintgeniez; Sascha David; Deborah Burstein; S Ananth Karumanchi; Isaac E Stillman; Zoltan Arany; Samir M Parikh Journal: J Clin Invest Date: 2011-09-01 Impact factor: 14.808
Authors: Wagner de Fátima Pereira; Gustavo Eustáquio A Brito-Melo; Cayo Antônio Soares de Almeida; Lázaro Lopes Moreira; Cleiton Willian Cordeiro; Thiago Guimarães Rosa Carvalho; Elvis Cueva Mateo; Ana Cristina Simões E Silva Journal: Inflamm Res Date: 2015-03-19 Impact factor: 4.575
Authors: Zsuzsanna K Zsengellér; Nika Aljinovic; Lisa A Teot; Mark Korson; Nancy Rodig; Jennifer L Sloan; Charles P Venditti; Gerard T Berry; Seymour Rosen Journal: Pediatr Nephrol Date: 2014-05-28 Impact factor: 3.714
Authors: R Bertelli; M Bodria; M Nobile; S Alloisio; R Barbieri; G Montobbio; P Patrone; G M Ghiggeri Journal: Clin Exp Immunol Date: 2011-07-15 Impact factor: 4.330
Authors: Maria A Mitry; Dimitri Laurent; Britny L Keith; Elizabeth Sira; Carol A Eisenberg; Leonard M Eisenberg; Sachindra Joshi; Sachin Gupte; John G Edwards Journal: Am J Physiol Cell Physiol Date: 2020-01-08 Impact factor: 4.249
Authors: Shuang Liang; Richard C Brundage; Pamala A Jacobson; Anne Blaes; Mark N Kirstein Journal: Br J Clin Pharmacol Date: 2016-06-03 Impact factor: 4.335