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Am J Physiol Renal Physiol (July 2, 2002). doi:10.1152/ajprenal.00118.2002
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Articles in PresS, published online ahead of print July 2, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00118.2002
Submitted on March 25, 2002
Accepted on June 27, 2002

Three GADD45 isoforms contribute to the hypertonic stress phenotype of murine renal inner medullary cells

Devulapalli Chakravarty1, Cai Qi2, Joan D. Ferraris2, Luis Michea2, Maurice B. Burg2, and Dietmar Kultz3*

1 The Whitney Laboratory, University of Florida, St. Augustine, FL, USA
2 Laboratory of Kidney and Electrolyte Metabolism, National Heart Lung and Blood Institute, Bethesda, MD, USA
3 The Whitney Laboratory, University of Florida, St. Augustine, FL, USA; Department of Animal Sciences, University of California, Davis, CA, USA

* To whom correspondence should be addressed. E-mail: dkueltz{at}ucdavis.edu.

Mammalian renal inner medullary (IM) cells routinely face and resist hypertonic stress. Such stress causes DNA damage, to which IM cells respond with cell cycle arrest. We report that three Growth Arrest and DNA Damage inducible 45 isoforms (GADD45{alpha}, GADDD45ß, GADD45{gamma}) are induced by acute hypertonicity in murine IM cells. Maximum induction occurs 16 - 18 h after the onset of hypertonicity. GADD45{gamma} is induced stronger (7-fold) than GADD45ß (3-fold) and GADD45{alpha} (2-fold). GADD45{alpha} and GADDD45ß protein induction is more pronounced and stable compared to the corresponding transcripts. Hypertonicity of various forms (NaCl, KCl, sorbitol, mannitol) always induces GADD45 transcripts, whereas non-hypertonic hyperosmolality (urea) has no effect. Actinomycin D does not prevent hypertonic GADD45 induction, indicating that mRNA stabilization is the mechanism. GADD45 induction patterns in IM cells exposed to ten different stresses suggest isoform-specificity, yet similar functions of individual isoforms during hypertonicity, heat shock, and heavy metal stress, when GADD45{gamma} induction is strongest (17-fold). These data associate all known GADD45 isoforms with the hypertonicity phenotype of renal IM cells.




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