Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression.
NAD(+)-dependent protein deacetylase Sirt1 regulates cellular apoptosis. We examined the role of Sirt1 in renal tubular cell apoptosis by using HK-2 cells, proximal tubular cell lines with or without reactive oxygen species (ROS), H(2)O(2). Without any ROS, Sirt1 inhibitors enhanced apoptosis and the expression of ROS scavenger, catalase, and Sirt1 overexpression downregulated catalase. When apoptosis was induced with H(2)O(2), Sirt1 was upregulated with the concomitant increase in catalase expression. Sirt1 overexpression rescued H(2)O(2)-induced apoptosis through the upregulation of catalase. H(2)O(2) induced the nuclear accumulation of forkhead transcription factor, FoxO3a and the gene silencing of FoxO3a enhanced H(2)O(2)-induced apoptosis. In conclusion, endogenous Sirt1 maintains cell survival by regulating catalase expression and by preventing the depletion of ROS required for cell survival. In contrast, excess ROS upregulates Sirt1, which activates FoxO3a and catalase leading to rescuing apoptosis. Thus, Sirt1 constitutes a determinant of renal tubular cell apoptosis by regulating cellular ROS levels.
Hasegawa
Kazuhiro
K
Department of Internal Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 1608582, Japan.
Wakino
Shu
S
Yoshioka
Kyoko
K
Tatematsu
Satoru
S
Hara
Yoshikazu
Y
Minakuchi
Hitoshi
H
Washida
Naoki
N
Tokuyama
Hirobumi
H
Hayashi
Koichi
K
Itoh
Hiroshi
H
D017209:Apoptosis; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000502:physiology*
C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D002374:Catalase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins