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This Article Full Text Full Text (PDF) All Versions of this Article: 288/1/F125    most recent 00041.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Hanigan, M. H. Articles by Lapus, M. G. Search for Related Content PubMed PubMed Citation Articles by Hanigan, M. H. Articles by Lapus, M. G.

Stress response inhibits the nephrotoxicity of cisplatin

¹Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; and ²Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Virginia Health Sciences Center, Charlottesville, Virginia

Submitted 31 January 2003 ; accepted in final form 1 September 2004

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 3-h cisplatin exposure. Further experiments revealed that minor variations in the sodium concentration among standard tissue culture media modulated cisplatin nephrotoxicity. NaCl 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.

kidney; cis-diamminedichloroplatinum; toxicity; proximal tubule; LLC-PK₁ cells