ACELL May 47/5

Yorek, Mark A., Joyce A. Dunlap, Wenli Liu, and William L. Lowe, Jr. Normalization of hyperosmoticinduced inositol uptake by renal and endothelial cells is regulated by NF-kB. Am J Physiol Cell Physiol 278: C1011– C1018, 2000.—Hyperosmolarity is a stress factor that has been shown to cause an increase in the transcription of the Na1-dependent myo-inositol cotransporter (SMIT). However, regulation of the reversion of SMIT mRNA levels and transporter activity following removal of hyperosmotic stress is less understood. Previously we have shown that postinduction normalization of SMIT mRNA levels and myo-inositol accumulation following removal of hyperosmotic stress is inhibited by actinomycin D and cycloheximide, suggesting that normalization requires RNA transcription and protein synthesis. We now demonstrate that removal of hyperosmotic stress causes an activation of the transcription factor NF-kB in renal and endothelial cells. Inhibiting NF-kB activation with pyrrolidine dithiocarbamate (PD) blocks the normalization of SMIT mRNA levels and myo-inositol accumulation on removal of the cells from hyperosmotic medium. These studies demonstrate that the downregulation of the myo-inositol transporter following reversal of hyperosmotic induction is regulated via the activation of NF-kB.