Hypertonic NaCl upregulated two sensitive and specific biochemical indices of apoptosis, caspase-3 activation and annexin V binding, in a time- and dose-dependent fashion in renal medullary mIMCD3 cells. Pretreatment with urea (200 mM for 30 min) protected from the proapoptotic effect of hypertonic stress (200 mosmol/kgH2O) in this model. The protective effect of urea was dose dependent and was effective even when applied a short time (≤1 h) following NaCl exposure; this protective effect was not observed in the nonrenal 3T3 cell line. In both mIMCD3 and 3T3 cells, urea failed to protect from the proapoptotic stressor, ultraviolet (UV)-B irradiation. The ability of urea to protect from hypertonic stress was approximately comparable to the protective effect of peptide mitogens epidermal growth factor and insulin-like growth factor (IGF), but it potentiated the IGF effect. Interestingly, the tyrosine kinase inhibitor, genistein, potentiated the proapoptotic effect of urea yet abrogated the proapoptotic effect of hypertonic stress. In aggregate, these data indicate that urea protects from the proapoptotic effect of hypertonic stress in a potentially cell type-specific and stimulus-specific fashion.
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