INHIBITORS OF RENAL CHLORIDE TRANSPORT DO NOT BLOCK TOXICANT-INDUCED CHLORIDE INFLUX IN THE PROXIMAL TUBULE

We have previously demonstrated that chloride influx occurs during the late stages of mitochondrial inhibitor-induced renal proximal tubule (RPT) cell injury. The purpose of this study was to determine if chloride influx is a common pathway in toxicant-induced cell injury and if inhibitors of renal chloride transport block the chloride influx. Chloride influx occurred in the late stages of RPT cell injury induced by the diverse toxicants mercuric chloride, t-butyl hydroperoxide, bromohydroquinone, and tetrafluoroethyl-L-cysteine. Specific inhibitors of known renal chloride transport did not prevent antimycin A-induced chloride influx. Toxicant-induced chloride influx occurred prior to cell swelling and decreasing the extracellular chloride concentration diminished toxicant-induced cell death. Thus, chloride influx is a common pathway in the late stages of toxic cell injury and does not occur through known mechanisms of renal chloride transport. Further, we propose that toxicant-induced chloride influx is mediated by a novel receptor related to the neuronal strychnine-sensitive glycine receptor and that chloride influx is a key step in cell swelling and lysis.