Chakravarty Devulapalli, Cai Qi, Ferraris Joan D, Michea Luis, Burg Maurice B, Kültz Dietmar
The Whitney Laboratory, University of Florida, St. Augustine, Florida 32080, USA.
Am J Physiol Renal Physiol. 2002 Nov;283(5):F1020-9. doi: 10.1152/ajprenal.00118.2002.
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 (GADD45) isoforms (GADD45alpha, GADDD45beta, and GADD45gamma) are induced by acute hypertonicity in murine IM cells. Maximum induction occurs 16-18 h after the onset of hypertonicity. GADD45gamma is induced more strongly (7-fold) than GADD45beta (3-fold) and GADD45alpha (2-fold). GADD45alpha and GADD45beta protein induction is more pronounced and stable compared with the corresponding transcripts. Hypertonicity of various forms (NaCl, KCl, sorbitol, or mannitol) always induces GADD45 transcripts, whereas nonhypertonic hyperosmolality (urea) has no effect. Actinomycin D does not prevent hypertonic GADD45 induction, indicating that mRNA stabilization is the mechanism that mediates this induction. GADD45 induction patterns in IM cells exposed to 10 different stresses suggest isoform specificity, but similar functions, of individual isoforms during hypertonicity, heat shock, and heavy metal stress, when GADD45gamma induction is strongest (17-fold). These data associate all known GADD45 isoforms with the hypertonicity phenotype of renal IM cells.
哺乳动物肾髓质内层（IM）细胞经常面临并抵抗高渗应激。这种应激会导致DNA损伤，IM细胞会通过细胞周期停滞来应对。我们报告称，三种生长停滞和DNA损伤诱导蛋白45（GADD45）亚型（GADD45α、GADD45β和GADD45γ）在小鼠IM细胞中由急性高渗诱导产生。高渗开始后16 - 18小时出现最大诱导。GADD45γ的诱导比GADD45β（3倍）和GADD45α（2倍）更强（7倍）。与相应转录本相比，GADD45α和GADD45β蛋白的诱导更明显且更稳定。各种形式（NaCl、KCl、山梨醇或甘露醇）的高渗总是诱导GADD45转录本，而非高渗性高渗（尿素）则没有影响。放线菌素D不能阻止高渗诱导的GADD45，这表明mRNA稳定化是介导这种诱导的机制。暴露于10种不同应激的IM细胞中的GADD45诱导模式表明，在高渗、热休克和重金属应激期间，当GADD45γ诱导最强（17倍）时，各个亚型具有亚型特异性但功能相似。这些数据将所有已知的GADD45亚型与肾IM细胞的高渗表型联系起来。
