Hypertonic stress response.

Mammalian renal inner medullary cells are normally exposed to extremely high NaCl concentrations. Remarkably, under these normal conditions, the high NaCl causes DNA damage and inhibits its repair, yet the cells survive and function both in cell culture and in vivo. The interstitial NaCl concentration in parts of a normal renal medulla can be 500 mM or more, depending on the species. Studies of how the cells survive and function despite this extreme stress have led to the discovery of protective adaptations, including accumulation of large amounts of organic osmolytes, which normalize cell volume and intracellular ionic strength, despite the hypertonicity of the high NaCl. Those adaptations, however, do not prevent DNA damage. High NaCl induces DNA breaks rapidly, and the DNA breaks persist even after the cells become adapted to the high NaCl. The adapted cells proliferate rapidly in cell culture and function adequately in vivo despite the DNA breaks. Both in cell culture and in vivo the breaks are rapidly repaired if the NaCl concentration is lowered. Although acute elevation of NaCl causes transient cell cycle arrest and, when the elevation is too extreme, apoptosis, proliferation of adapted cells is not arrested in culture and apoptosis is not evident either in culture or in vivo. Further, high NaCl impairs activation of several components of the classical DNA damage response such as Mre11, H2AX and Chk1 leading to inhibition of DNA repair. Nevertheless, other regular participants in the DNA damage response, such as Gadd45a, Gadd153, p53, Hsp70, and ATM are still upregulated by high NaCl. How high NaCl causes the DNA breaks and how the cells survive them is conjectural at this point. We discuss possible answers to these questions, based on current knowledge about induction and processing of DNA breaks.