Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury.
The mitochondria are a critical target for cisplatin-associated nephrotoxicity. Though nitric oxide formation has been implicated in the toxicity of cisplatin, this formation has not so far been related to a possible activation of mitochondrial nitric oxide synthase (mNOS). We show here that the upregulation of oxide mNOS and peroxynitrite formation in cisplatin treatment are key events that influence the development of the harmful parameters described in cisplatin-associated kidney failure. We confirm this by isolating the mitochondrial fraction of the kidney and across different access routes such as the use of a specific inhibitor of neuronal NOS, L-NPA, a peroxynitrite scavenger, FeTMPyP, and a peroxynitrite donor, SIN-1. The in vitro studies corroborated the information obtained in the in vivo experiments. The administration of cisplatin reveals a clear upregulation in the transcription of neuronal NOS and an increase in the levels of nitrites in the mitochondrial fractions of the kidneys. The upregulated transcription directly affects the cytoskeleton structure and the apoptosis. The inhibition of neuronal NOS reduces the levels of nitrites, cell death, and cytoskeleton derangement. Peroxynitrite is involved in the mechanism promoting the NOS transcription. In addition, in controls SIN-1 imitates the effects of cisplatin. In summary, we demonstrate that upregulation of mNOS in cisplatin treatment is a key component in both the initiation and the spread of cisplatin-associated damage in the kidney. Furthermore, peroxynitrite formation is directly involved in this process.
Jung
Michaela
M
Department of Ischemia and Inflammation, Instituto de Investigaciones Biomédicas, IIBB-CSIC-IDIBAPS, C/ Rosselló, 161, 7(a), 08036 Barcelona, Spain.
Hotter
Georgina
G
Viñas
Jose Luis
JL
Sola
Anna
A
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004396:Coloring Agents; D045304:Cytochromes c / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D007150:Immunohistochemistry; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052248:Nitric Oxide Synthase Type I / Q000096:biosynthesis / Q000235:genetics; D030421:Peroxynitrous Acid / Q000378:metabolism*; D010590:Phalloidine; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D004396:Coloring Agents; D012333:RNA, Messenger; D030421:Peroxynitrous Acid; D010590:Phalloidine; D009569:Nitric Oxide; C002385:linsidomine; D045304:Cytochromes c; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D053148:Caspase 3; D002945:Cisplatin