Sodium-dependent glucose transporter reduces peroxynitrite and cell injury caused by cisplatin in renal tubular epithelial cells.
Cisplatin causes nephropathy accompanied by two types of cell death, necrosis and apoptosis, according to its dosage. The mechanisms of necrosis are still unclear. In this study, we examined how high doses of cisplatin induce cell injury and whether a high affinity sodium-dependent glucose transporter (SGLT1) has a cytoprotective function in renal epithelial LLC-PK(1) cells. Cisplatin decreased in transepithelial electrical resistance (TER) and increased in the number of necrotic dead cells in a time dependent manner. Phloridzin, a potent SGLT1 inhibitor, enhanced both TER decrease and increase of necrotic dead cells caused by cisplatin. Cisplatin increased in the intracellular nitric oxide, superoxide anion and peroxynitrite productions. Phloridzin enhanced the peroxynitrite production caused by cisplatin. The intracellular diffusion of ZO-1 and TER decrease caused by cisplatin were inhibited by N-nitro-l-arginine methyl ester, a nitric oxide synthase inhibitor. Protein kinase C was not involved in the cisplatin-induced injury. 5,10,15,20-tetrakis-(4-sulfonatophenyl)-porphyrinato iron (III) and reduced glutathione, peroxynitrite scavengers, inhibited the cisplatin-induced ZO-1 diffusion, TER decrease, and increase of necrotic dead cells. These results suggest that peroxynitrite is a key mediator in the nephrotoxicity caused by high doses of cisplatin. SGLT1 endogenously carries out the cytoprotective function by the reduction of peroxynitrite production.
Ikari
Akira
A
Department of Environmental Biochemistry and Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. ikari@u-shizouka-ken.ac.jp
Nagatani
Yoshiaki
Y
Tsukimoto
Mitsutoshi
M
Harada
Hitoshi
H
Miwa
Masao
M
Takagi
Kuniaki
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D007684:Kidney Tubules / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced; D009569:Nitric Oxide / Q000096:biosynthesis; D030421:Peroxynitrous Acid / Q000096:biosynthesis*; D051269:Sodium-Glucose Transporter 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013552:Swine
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D051269:Sodium-Glucose Transporter 1; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D002945:Cisplatin