Abstract
Cisplatin is a potent antitumor drug but its clinical use is limited by nephrotoxic side effects. Cellular and molecular mechanisms of cisplatin-induced nephrotoxicity have not been known well. We examined whether nitric oxide (NO) is involved in the cisplatin-induced nephrotoxicity and whether sodium-dependent glucose transporter (SGLT1) has cytoprotecitve effect. In porcine renal epithelial LLC-PK1 cells, cisplatin induced necrosis at high concentration as assessed by propidium iodide stain. The proportion of necrosis in sub-confluent condition is higher than that in the confluent condition. This cell line induces expression of SGLT1 after reaching the confluent condition. Interestingly, phloridzin, a potent inhibitor of SGLT1, enhanced cisplatin-induced necrosis in the confluent condition. Next, we checked the effect of cisplatin on transepithelial electrical resistance (TER). Cisplatin decreased TER in a time-dependent manner and disrupted ZO-1 distribution at tight junction. Phloridzin enhanced the decrease of TER by cisplatin. Cisplatin increased the productions of reactive oxygen species. Among them, NO production was enhanced by phloridzin. The cisplatin-induced decrease of TER was partially blocked by NG-nitro-L-arginine, a NO synthase inhibitor. These results suggest that NO is concerned in the cisplatin-induced nephrotoxicity and SGLT1 endogenously reduces cellular injury mediated by suppression of NO production. [Jpn J Physiol 55 Suppl:S70 (2005)]
