Cell cycle delay and apoptosis in response to osmotic stress

As part of the urinary concentrating mechanism, renal inner medulla cells m ay be exposed to extremely variable NaCl and urea concentrations that can r each very high levels. A number of studies, reviewed herein, aim to underst and how such osmotic stress affects the cells and what protective mechanism s might exist. The majority of these studies are done on inner medullary ep ithelial cells that grow continuously in tissue culture (mIMCD3). Cells gro wn at 300 mosmol/kg survive increase to 500 mosmol/ka by adding NaCl or ure a, but only after a growth arrest of similar to 24 h. At a higher osmolalit y (650-700 mosmol/kg) most cells die within hours by apoptosis. The cells b oth in vitro and in vivo adapt to high osmolality by a number of mechanisms , including accumulation of variety of organic osmolytes and induction of h eat shock proteins. The cell cycle delay results from blocks at the G1 and G2/M checkpoints and slowing during S. After adding NaCl, but not urea, the amount and transcriptional activity of p53 (the tumor suppressor protein) increases. The p53 is phosphorylated on ser-15 and is transcriptionally act ive at 500 mosmol/kg (associated with cell survival), but not at 700 mosmol /ka (associated with apoptosis). Reduction of p53 expression by p53 antisen se oligonucleotide increases sensitivity of renal cells in culture to hyper osmotic stress caused by NaCl. The possible mechanisms of the protection ac tion of p53 against hypertonic stress are discussed. (C) 2001 Published by Elsevier Science Inc.