Submitted on January 31, 2003
Accepted on September 1, 2004
Stress Response Inhibits the Nephrotoxicity of Cisplatin
Marie H. Hanigan1*, Mei Deng2, Lei Zhang1, Peyton T. Taylor Jr2, and Maia G. Lapus1
1 Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
2 Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Virginia Health Sciences Center, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: marie-hanigan{at}ouhsc.edu.
Salt-loading and saline hydration are used to protect patients from cisplatin-induced nephrotoxicity. The mechanism by which salt exerts its protective effect is unknown. As part of an ongoing study of cisplatin nephrotoxicity, an in vitro assay system was developed that models the in vivo exposure and response of proximal tubule cells to cisplatin. In this study, it was discovered that the toxicity of cisplatin toward LLC-PK1 cells varied dramatically according to the tissue culture media used for the 3 hr cisplatin exposure. Further experiments revealed that minor variations in the
sodium concentration among standard tissue culture media modulated cisplatin nephrotoxicity. Sodium chloride has been shown to protect against cisplatin-induced nephrotoxicity in vivo, but has never before been demonstrated in vitro. NaCl did not alter the cellular accumulation of cisplatin. NaCl altered the osmolarity of the external media and its effect was replicated by substituting equiosmolar concentrations of impermeant anions or cations. The change in osmolarity triggered
a stress response within the cell that modulated sensitivity to cisplatin. These data resolve several
long-standing controversies regarding the mechanism by which salt-loading protects the kidney from cisplatin-induced nephrotoxicity.
