Up-regulation of aldose reductase expression mediated by phosphatidylinositol 3-kinase/Akt and Nrf2 is involved in the protective effect of curcumin against oxidative damage.
Up-regulation of aldose reductase (AR) by reactive oxygen species (ROS) and aldehyde derivatives has been observed in vascular smooth muscle cells. However, the pathophysiological consequences of the induction of AR in vascular tissues are not fully elucidated. Herein we report that an herb-derived polyphenolic compound, curcumin, elicited a dose- and time-dependent increase in AR expression. Inhibition of phosphatidylinositol 3-kinase (PI3K) and p38 mitogen-activated protein kinase (MAPK) significantly suppressed the curcumin-augmented mRNA levels and promoter activity of the AR gene. Luciferase reporter assays indicated that an osmotic response element in the promoter was essential for the responsiveness to curcumin. Curcumin accelerated the nuclear translocation of nuclear factor-erythroid 2-related factor 2 (Nrf2), and overexpression of Nrf2, but not the dominant negative Nrf2, enhanced the promoter activity of the AR gene. Cells preincubated with curcumin demonstrated resistance to ROS-induced apoptotic death. These effects were significantly attenuated in the presence of AR inhibitors or small interfering RNAs, indicating a protective role for AR against ROS-induced cell damage. Taken together, the activation of PI3K and p38 MAPK by curcumin augmented the expression of the AR gene via Nrf2, and increased AR activity may be an important cellular response against oxidative stress.
Kang
Eun Sil
ES
Department of Pharmacology, Gyeongsang Institute of Health Science, College of Medicine, Gyeongsang National University, 92 Chilam-Dong, Jinju 660-751, Korea.
Woo
Im Sun
IS
Kim
Hyo Jung
HJ
Eun
So Young
SY
Paek
Kyung Shin
KS
Kim
Hye Jung
HJ
Chang
Ki Churl
KC
Lee
Jae Heun
JH
Lee
Hoon Taek
HT
Kim
Jin-Hoi
JH
Nishinaka
Toru
T
Yabe-Nishimura
Chihiro
C
Seo
Han Geuk
HG
D000449:Aldehyde Reductase / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism
D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000449:Aldehyde Reductase; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D048051:p38 Mitogen-Activated Protein Kinases; D003474:Curcumin