Search

Activation of the unfolded protein response (UPR) has been suggested to attenuate renal ischemia-reperfusion (I/R) injury. We recently found a compound, namely BIX, that activated the UPR selectively through the activating transcription factor 6 pathway. This study examined the effect of BIX on renal I/R injury in mice. BIX selectively up-regulated renal BiP mRNA and protein. Pretreatment with BIX significantly ameliorated renal I/R injury. Coadministration of BIX and tunicamycin, a non-selective UPR inducer, provided no additional protection. Our results suggest that the UPR activation by BIX leads to a novel drug therapy against renal I/R injury. Keywords:: renal ischemia-reperfusion injury, endoplasmic reticulum (ER) stress, unfolded protein response

アルツハイマー病，パーキンソン病を代表とする神経変性疾患は，進行性の神経細胞死という解剖学的所見を共通の特徴とする疾患であるが，その発症原因は不明であり，充分に有効な治療法・治療薬は未だ見いだされていない．また，脳虚血などの脳血管性疾患については，脳血流の低下あるいは再灌流をトリガーとして神経細胞死が惹起されることは明白であるものの，未だ著効な治療法・治療薬は明らかではない．このような背景のもと，これら神経変性疾患および脳血管性疾患に共通する「神経細胞死」という現象に関わる分子機序の解明を通して新たな治療法開発にアプローチしようという試みが，国内外ともに最近の研究の潮流となりつつある．本稿では，第80回日本薬理学会年会において開催された表題のシンポジウムでの講演より，神経変性疾患および脳血管性疾患の病態解明ならびに新規治療法の開発に大きく貢献しうる神経細胞死メカニズムの最先端研究を紹介する．

The endoplasmic reticulum (ER) is susceptible to various stresses that provoke the accumulation of unfolded proteins in the ER. Excessive or long-termed stresses in the ER result in apoptotic cell death involving activation of caspase-12 and -3 and the Ask-1-JNK pathway. Eukaryotic cells can adapt for survival to deal with an accumulation of unfolded proteins in the ER by increasing transcription of genes encoding ER-resident chaperones such as GRP78/BiP to facilitate protein folding. The induction system is termed the unfolded protein response (UPR). It has been reported that IRE1 and PERK, transmembrane kinases, and ATF6, a transmembrane transcription factor, are mediators of the UPR through sensing accumulation of unfolded proteins. Cell fates after ER stress are regulated by the balance of both apoptosis and the UPR signaling. In the nervous systems, astrocytes are well known to be resistant to ER stresses induced by ischemia and hypoxia. These findings raise the possibility that astrocytes possess a novel UPR signaling different from that of neuronal cells. Recently, we identified a novel ER stress sensor, OASIS, which is specifically expressed in astrocytes. This protein is a transmembrane protein containing the bZIP domain. The functional analyses of OASIS showed that 1) it was cleaved within the ER membrane in response to the ER stress, 2) overexpression of OASIS induced the transcription of GRP78/BiP mRNA through the activation of cyclic AMP responsive element (CRE) and ER stress responsive element (ERSE), and 3) its stable cell lines were resistant to ER stress compared with the control cells. These results indicate that the ER-resident transcription factor OASIS may be a candidate for leading astrocytes to protect against ER stress.