ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death.
The 150 kDa oxygen-regulated protein (ORP150) is an inducible endoplasmic reticulum (ER) chaperone with cytoprotective properties in settings of cell stress, such as ischemia/reperfusion (I/R). Renal tissue from patients with acute renal failure displayed strong induction of ORP150 in tubular epithelium. In a rodent model of renal I/R injury, ORP150 was expressed in both the ischemic and contralateral kidney, principally in the thick ascending loop of Henle (TAL) and distal tubules. Cultured renal epithelial cells exposed to hypoxic or hyperosmotic conditions displayed induction of ORP150. Renal tubular epithelial cells stably transfected with ORP150 sense or antisense cDNA displayed a strong correlation between ORP150 expression and vulnerability to hypoxic/osmotic stress; higher levels of ORP150 were protective, whereas lower levels increased susceptibility to cell death. Compared with nontransgenic controls, transgenic mice overexpressing ORP150 subjected to renal I/R displayed a blunted rise of serum creatinine and blood urea nitrogen, and enhanced survival of TAL, consistent with cytoprotection. In contrast, heterozygous ORP150+/- mice, with lower levels of ORP150, showed enhanced renal injury. These data are consistent with the possibility that ORP150 exerts cytoprotective effects in renal tubular epithelia subjected to I/R injury and suggest a key role for ER stress in the renal tubular response to acute renal failure.
Bando
Yoshio
Y
Department of Anatomy I, Asahikawa Medical College, Asahikawa, Hokkaido, Japan. ybando@asahikawa-med.ac.jp
Tsukamoto
Yoshitane
Y
Katayama
Taichi
T
Ozawa
Kentaro
K
Kitao
Yasuko
Y
Hori
Osamu
O
Stern
David M
DM
Yamauchi
Atsushi
A
Ogawa
Satoshi
S
D000818:Animals; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005665:Furosemide / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D009392:Nephrectomy; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*
D061945:Caspase Inhibitors; D018840:HSP70 Heat-Shock Proteins; D011506:Proteins; D012333:RNA, Messenger; C050087:oxygen-regulated proteins; D005665:Furosemide; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases