title: DNA damage and osmotic regulation in the kidney.
abstract: Renal medullary cells normally are exposed to extraordinarily high interstitial NaCl concentration as part of the urinary concentrating mechanism, yet they survive and function. Acute elevation of NaCl to a moderate level causes transient cell cycle arrest in culture. Higher levels of NaCl, within the range found in the inner medulla, cause apoptosis. Recently, it was surprising to discover that even moderately high levels of NaCl cause DNA double-strand breaks. The DNA breaks persist in cultured cells that are proliferating rapidly after adaptation to high NaCl, and DNA breaks normally are present in the renal inner medulla in vivo. High NaCl inhibits repair of broken DNA both in culture and in vivo, but the DNA is rapidly repaired if the level of NaCl is reduced. The inhibition of DNA repair is associated with suppressed activity of some DNA damage-response proteins like Mre11, Chk1, and H2AX but not that of others, like GADD45, p53, ataxia telangiectasia-mutated kinase (ATM), and Ku86. In this review, we consider possible mechanisms by which the renal cells escape the known dangerous consequences of persistent DNA damage. Furthermore, we consider that the persistent DNA damage may be a sensor of hypertonicity that activates ATM kinase to provide a signal that contributes to protective osmotic regulation.
authors.affiliation: Laboratory of Kidney and Electrolyte Metabolism, National Heart, Lung, and Blood Institute, Department of Health and Human Services, Bethesda, MD 20892-1603, USA.
authors.forename: Natalia I
authors.initials: NI
authors.lastname: Dmitrieva
authors.forename: Maurice B
authors.initials: MB
authors.lastname: Burg
authors.forename: Joan D
authors.initials: JD
authors.lastname: Ferraris
mesh_terms: D000818:Animals; D004249:DNA Damage / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007679:Kidney Medulla / Q000502:physiology*; D014882:Water-Electrolyte Balance / Q000502:physiology*