TY - JOUR
T1 - Cisplatin Nephrotoxicity Involves Mitochondrial Injury with Impaired Tubular Mitochondrial Enzyme Activity
AU - Zsengellér, Zsuzsanna K.
AU - Ellezian, Lena
AU - Brown, Dan
AU - Horváth, Béla
AU - Mukhopadhyay, Partha
AU - Kalyanaraman, Balaraman
AU - Parikh, Samir M.
AU - Karumanchi, S. Ananth
AU - Stillman, Isaac E.
AU - Pacher, Pál
PY - 2012/7
Y1 - 2012/7
N2 - 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.
AB - 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.
KW - cisplatin
KW - cytochrome c oxidase
KW - functional electron microscopy
KW - mitochondria
KW - nephrotoxicity
UR - http://www.scopus.com/inward/record.url?scp=84865847205&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84865847205&partnerID=8YFLogxK
U2 - 10.1369/0022155412446227
DO - 10.1369/0022155412446227
M3 - Article
C2 - 22511597
AN - SCOPUS:84865847205
SN - 0022-1554
VL - 60
SP - 521
EP - 529
JO - Journal of Histochemistry and Cytochemistry
JF - Journal of Histochemistry and Cytochemistry
IS - 7
ER -