Cisplatin nephrotoxicity involves mitochondrial injury with impaired tubular mitochondrial enzyme activity. J Histochem Cytochem 2012 Jul;60(7):521-9
Date
04/19/2012Pubmed ID
22511597Pubmed Central ID
PMC3460350DOI
10.1369/0022155412446227Scopus ID
2-s2.0-84865847205 (requires institutional sign-in at Scopus site) 102 CitationsAbstract
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.
Author List
Zsengellér ZK, Ellezian L, Brown D, Horváth B, Mukhopadhyay P, Kalyanaraman B, Parikh SM, Karumanchi SA, Stillman IE, Pacher PAuthor
Balaraman Kalyanaraman PhD Professor in the Biophysics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Acute Kidney InjuryAnimals
Cisplatin
Electron Transport Complex IV
Immunohistochemistry
Kidney Tubules, Proximal
Male
Mice
Mice, Inbred C57BL
Mitochondria
Reactive Oxygen Species