Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C δ in a mouse model of diabetic retinopathy

Park, Jeongsook; Kim, Hwajin; Park, So Yun; Lim, Sun Woo; Kim, Yoon Sook; Lee, Dong Hoon; Roh, Gu Seob; Kang, Sang Soo; Cho, Gyeong Jae; Jeong, Bo-Young; Kwon, Hyug Moo; Choi, Wan Sung

doi:10.1016/j.exer.2014.03.001

Cited by 18 publications

(17 citation statements)

References 50 publications

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“…NFAT5 is the major transcription factor that regulates the cell survival in osmotic stress [32]. NFAT5 activity was shown to contribute to the hyperosmotic expression of the VEGF-A gene in RPE cells [31] and to the neuronal degeneration in the retina of diabetic rats [45]. Here, we found that the hyperosmotic (Fig.…”

Section: Discussionsupporting

confidence: 54%

Osmotic induction of placental growth factor in retinal pigment epithelial cells in vitro: contribution of NFAT5 activity

et al. 2016

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One risk factor of neovascular age-related macular degeneration is systemic hypertension; hypertension is mainly caused by extracellular hyperosmolarity after consumption of dietary salt. In retinal pigment epithelial (RPE) cells, high extracellular osmolarity induces vascular endothelial growth factor (VEGF)-A (Hollborn et al. in Mol Vis 21:360-377, 2015). The aim of the present study was to determine whether extracellular hyperosmolarity and chemical hypoxia trigger the expression of further VEGF family members including placental growth factor (PlGF) in human RPE cells. Hyperosmotic media were made up by addition of 100 mM NaCl or sucrose. Chemical hypoxia was induced by CoCl2. Gene expression was quantified by real-time RT-PCR, and secretion of PlGF-2 was investigated with ELISA. Nuclear factor of activated T cell 5 (NFAT5) was depleted using siRNA. Extracellular hyperosmolarity triggered expression of VEGF-A, VEGF-D, and PlGF genes, and secretion of PlGF-2. Hypoosmolarity decreased PlGF gene expression. Hypoxia induced expression of VEGF-A, VEGF-B, VEGF-D, and PlGF genes. Extracellular hyperosmolarity and hypoxia produced additive PlGF gene expression. Both hyperosmolarity and hypoxia induced expression of KDR and FLT-4 receptor genes, while hyperosmolarity caused neuropilin-2 and hypoxia neuropilin-1 gene expression. The hyperosmotic, but not the hypoxic, PlGF gene expression was in part mediated by NFAT5. The expression of PlGF in RPE cells depends on the extracellular osmolarity. The data suggest that high consumption of dietary salt may exacerbate the angiogenic response of RPE cells in the hypoxic retina via transcriptional activation of various VEGF family member genes.

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Section: Discussionsupporting

confidence: 54%

Osmotic induction of placental growth factor in retinal pigment epithelial cells in vitro: contribution of NFAT5 activity

et al. 2016

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“…To achieve this goal, two different agents, 25 mM glucose and 100 mM NaCl, revealed to upregulate NFAT5 expression [28,[73][74][75][76], have been employed on U937 cells (Fig. 1).…”

Section: H Of 100 MM Nacl Treatment Is a Convenient Osmotic Stressmentioning

confidence: 99%

SIRT1 contributes to aldose reductase expression through modulating NFAT5 under osmotic stress: In vitro and in silico insights

Timuçin

Bodur

Başağa

2015

Cellular Signalling

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“…Memory impairment in aged rats with diabetes is exacerbated by inhibiting the signaling of the transcription factor nuclear factor-kappa B (NF-κB) in the hippocampus 9 . However, downregulation of another member of the Rel family of transcription factors, the tonicity-responsive enhancer binding protein (TonEBP, also known as nuclear factor of activated T cells 5) 10 , prevents neuronal death in animal models of streptozotocin (STZ)-induced diabetic retinopathy 11 , 12 . TonEBP is abundantly expressed in the liver, heart, brain, and kidney, as well as in activated T cells 13 – 15 , and is reduced under hypoosmotic conditions 16 .…”

Section: Introductionmentioning

confidence: 99%

TonEBP/NFAT5 haploinsufficiency attenuates hippocampal inflammation in high-fat diet/streptozotocin-induced diabetic mice

Lee

Jeong

Kim

et al. 2017

Sci Rep

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Recent studies have shown that overexpression of tonicity-responsive enhancer binding protein (TonEBP) is associated with many inflammatory diseases, including diabetes mellitus, which causes neuroinflammation in the hippocampus as well as hepatic steatosis. However, the exact mechanism in diabetic neuroinflammation is unknown. We report that haploinsufficiency of TonEBP inhibits hepatic and hippocampal high-mobility group box-1 (HMGB1) expression in diabetic mice. Here, mice were fed a high-fat diet (HFD) for 16 weeks and received an intraperitoneal injection of 100 mg/kg streptozotocin (STZ) and followed by continued HFD feeding for an additional 4 weeks to induce hyperglycemia and hepatic steatosis. Compared with wild-type diabetic mice, diabetic TonEBP+/− mice showed decreased body weight, fat mass, hepatic steatosis, and macrophage infiltration. We also found that adipogenesis and HMGB1 expression in the liver and hippocampus were lower in diabetic TonEBP+/− mice compared with the wild type. Furthermore, iba-1 immunoreactivity in the hippocampus was decreased in diabetic TonEBP+/− mice compared with that in the wild type. Our findings suggest that TonEBP haploinsufficiency suppresses diabetes-associated hepatic steatosis and neuroinflammation.

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Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C δ in a mouse model of diabetic retinopathy

Cited by 18 publications

References 50 publications

Osmotic induction of placental growth factor in retinal pigment epithelial cells in vitro: contribution of NFAT5 activity

Osmotic induction of placental growth factor in retinal pigment epithelial cells in vitro: contribution of NFAT5 activity

SIRT1 contributes to aldose reductase expression through modulating NFAT5 under osmotic stress: In vitro and in silico insights

TonEBP/NFAT5 haploinsufficiency attenuates hippocampal inflammation in high-fat diet/streptozotocin-induced diabetic mice

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