title: Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity.
abstract: Cisplatin is a widely used antineoplastic agent. However, its major limitation is dose-dependent nephrotoxicity whose precise mechanism is poorly understood. Recent studies have suggested that mitochondrial dysfunction in tubular epithelium contributes to cisplatin-induced nephrotoxicity. Here the authors extend those findings by describing the role of an important electron transport chain enzyme, cytochrome c oxidase (COX). Immunohistochemistry for COX 1 protein demonstrated that, in response to cisplatin, expression was mostly maintained in focally damaged tubular epithelium. In contrast, COX enzyme activity in proximal tubules (by light microscopy) was decreased. Ultrastructural analysis of the cortex and outer stripe of the outer medulla showed decreased mitochondrial mass, disruption of cristae, and extensive mitochondrial swelling in proximal tubular epithelium. Functional electron microscopy showed that COX enzyme activity was decreased in the remaining mitochondria in the proximal tubules but maintained in distal tubules. In summary, cisplatin-induced nephrotoxicity is associated with structural and functional damage to the mitochondria. More broadly, using functional electron microscopy to measure mitochondrial enzyme activity may generate mechanistic insights across a spectrum of renal disorders.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. zzsengel@bidmc.harvard.edu
authors.forename: Zsuzsanna K
authors.initials: ZK
authors.lastname: Zsengellér
authors.forename: Lena
authors.initials: L
authors.lastname: Ellezian
authors.forename: Dan
authors.initials: D
authors.lastname: Brown
authors.forename: Béla
authors.initials: B
authors.lastname: Horváth
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Balaraman
authors.initials: B
authors.lastname: Kalyanaraman
authors.forename: Samir M
authors.initials: SM
authors.lastname: Parikh
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
authors.forename: Isaac E
authors.initials: IE
authors.lastname: Stillman
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002945:Cisplatin / Q000633:toxicity*; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007150:Immunohistochemistry; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D003576:Electron Transport Complex IV; D002945:Cisplatin