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

• Published in: Free radical biology & medicine Vol. 43; no. 4; pp. 535 - 545
• Main Authors: Kang, Eun Sil, Woo, Im Sun, Kim, Hyo Jung, Eun, So Young, Paek, Kyung Shin, Kim, Hye Jung, Chang, Ki Churl, Lee, Jae Heun, Lee, Hoon Taek, Kim, Jin-Hoi, Nishinaka, Toru, Yabe-Nishimura, Chihiro, Seo, Han Geuk
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-08-2007
• Subjects: Aldehyde Reductase - biosynthesis; Aldehyde Reductase - drug effects; Aldehyde Reductase - genetics; Aldose reductase; Animals; Antioxidants - pharmacology; Apoptosis; Apoptosis - drug effects; Blotting, Northern; Blotting, Western; Cells, Cultured; Curcumin; Curcumin - pharmacology; Dose-Response Relationship, Drug; Free radicals; Gene Expression - drug effects; Gene Expression Regulation, Enzymologic - drug effects; In Situ Nick-End Labeling; MAPK; Microscopy, Confocal; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Mutagenesis, Site-Directed; NF-E2-Related Factor 2 - metabolism; Nrf2; Oncogene Protein v-akt - metabolism; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - physiology; p38 Mitogen-Activated Protein Kinases - drug effects; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Promoter Regions, Genetic; Rats; Reactive Oxygen Species - metabolism; RNA, Messenger - analysis; RNA, Small Interfering; Up-Regulation; Vascular smooth muscle cells; Oxidative stress; ORE; Free radicals; MAPK; AR; GOX; DN-Nrf2; TUNEL; PI3K; Aldose reductase; Nrf2; ROS; Curcumin; HBSS; VSMC; Vascular smooth muscle cells; ERK; Apoptosis
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2007.05.006

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.