The response of renal inner medullary (IM) collecting duct cells (mIMCD3) to high NaCl involves increased expression of Gadd45 and p53, both of which have important effects on growth and survival of the cells. However, mIMCD3 cells, being immortalized by SV40, proliferate rapidly, which is known to sensitize cells to high NaCl, whereas IM cells in situ proliferate very slowly and survive much higher levels of NaCl. In the present studies we have examined the importance of Gadd45 and p53 for survival of normal IM cells in their usual high NaCl environment by using more slowly proliferating second passage mouse inner medullary epithelial (p2mIME) cells and comparing cells from wild type and gene knockout mice. Acutely elevating NaCl (and/or urea) reduces Gadd45a, but increases Gadd45b and Gadd45g mRNA, depending on the mix of NaCl and urea and the rate of increase of osmolality. Nevertheless, p2mIME cells from Gadd45b^-/-, Gadd45g^-/-, and Gadd45b,g^-/- mice survive elevation of NaCl (or urea) essentially the same as do wild type cells. p53 ^-/- cells do not tolerate as high a concentration of NaCl (or urea) as p53^+/+ cells, but urinary concentrating ability of p53^-/- mice is normal, as is histology of inner medullas from p53^-/- and Gadd45a,b,g^-/- mice. Thus, although Gadd45 and p53 may play roles in osmotically stressed mIMCD3 cells, we do not find that their expression makes an important difference, either for Gadd45 in slower proliferating p2mIME cells or for Gadd45 or p53 in normal inner medullary epithelial cells in situ.