A protective role of unfolded protein response in mouse ischemic acute kidney injury.
Although renal ischemia-reperfusion is known to activate the unfolded protein response, the renal site and role of activation of this response following the insult in vivo remains largely unknown. Here we studied the renal spatio-temporal expression pattern of glucose-regulated protein (GRP) 78, a central regulator of the unfolded protein response network, following renal ischemia-reperfusion and the effects of the specific chemical unfolded protein response inducers, tunicamycin and thapsigargin, on renal ischemia-reperfusion injury in mice. Renal ischemia-reperfusion resulted in expression of the spliced form of the X-box binding protein-1 (XBP-1s) transcript, an unfolded protein response target, at 1 and 2 h after the insult. This response was followed by an increase in the GRP78 transcript and protein. The increased amount of GRP78 protein after ischemia-reperfusion was largely localized in proximal tubule cells. Pretreatment with tunicamycin or thapsigargin significantly ameliorated renal dysfunction and injury after ischemia-reperfusion. Taken together with these results, the unfolded protein response was activated following renal ischemia-reperfusion at sites that are susceptible to ischemia-reperfusion injury, and this activation had a protective effect against renal ischemia-reperfusion injury in vivo. Molecules involved in the unfolded protein response may offer new opportunities for pharmacological intervention against renal ischemia-reperfusion injury, which is an important cause of acute kidney injury.
Prachasilchai
Worapat
W
Department of Veterinary Pharmacology, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.
Sonoda
Hiroko
H
Yokota-Ikeda
Naoko
N
Oshikawa
Sayaka
S
Aikawa
Chie
C
Uchida
Kazuyuki
K
Ito
Katsuaki
K
Kudo
Takashi
T
Imaizumi
Kazunori
K
Ikeda
Masahiro
M
D000818:Animals; D015153:Blotting, Western; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000188:drug therapy / Q000473:pathology*; D007677:Kidney Function Tests; D008297:Male; D051379:Mice; D018832:Molecular Chaperones / Q000096:biosynthesis / Q000235:genetics; D017510:Protein Folding; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D012079:Renal Circulation / Q000502:physiology; D015427:Reperfusion Injury / Q000188:drug therapy / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014415:Tunicamycin / Q000494:pharmacology; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D004791:Enzyme Inhibitors; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D014415:Tunicamycin; D019284:Thapsigargin