The PI3K/Akt Signaling Pathway Mediates the High Glucose-Induced Expression of Extracellular Matrix Molecules in Human Retinal Pigment Epithelial Cells

Dong, Qian; Zhang, Guoming; Xu, Xun; Wang, Liya

doi:10.1155/2015/920280

Cited by 35 publications

(30 citation statements)

References 27 publications

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“…Moreover, in cultured human renal cortex tissue, hanging drop medium with a high concentration of glucose increased NOS1 expression and stimulated the NOS1 phosphorylation at Ser1417. Regarding potential mechanisms, on the basis of the related literature, we speculate that glucose upregulates NOS1 expression and phosphorylates NOS1 via the PI3K/Akt [65][66][67][68][69] and/or cAMP/PKA [70][71][72][73][74] pathways.…”

Section: Glucose-induced Hyperfiltration Is Mediated By Macula Densa mentioning

confidence: 90%

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

Zhang¹,

Jin²,

Jiang³

et al. 2019

JASN

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Background Glomerular hyperfiltration is common in early diabetes and is considered a risk factor for later diabetic nephropathy. We propose that sodium-glucose cotransporter 1 (SGLT1) senses increases in luminal glucose at the macula densa, enhancing generation of neuronal nitric oxide synthase 1 (NOS1)dependent nitric oxide (NO) in the macula densa and blunting the tubuloglomerular feedback (TGF) response, thereby promoting the rise in GFR. Methods We used microperfusion, micropuncture, and renal clearance of FITC-inulin to examine the effects of tubular glucose on NO generation at the macula densa, TGF, and GFR in wild-type and macula densa-specific NOS1 knockout mice. Results Acute intravenous injection of glucose induced hyperglycemia and glucosuria with increased GFR in mice. We found that tubular glucose blunts the TGF response in vivo and in vitro and stimulates NO generation at the macula densa. We also showed that SGLT1 is expressed at the macula densa; in the presence of tubular glucose, SGLT1 inhibits TGF and NO generation, but this action is blocked when the SGLT1 inhibitor KGA-2727 is present. In addition, we demonstrated that glucose increases NOS1 expression and NOS1 phosphorylation at Ser1417 in mouse renal cortex and cultured human kidney tissue. In macula densa-specific NOS1 knockout mice, glucose had no effect on NO generation, TGF, and GFR. Conclusions We identified a novel mechanism of acute hyperglycemia-induced hyperfiltration wherein increases in luminal glucose at the macula densa upregulate the expression and activity of NOS1 via SGLT1, blunting the TGF response and promoting glomerular hyperfiltration.

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Section: Glucose-induced Hyperfiltration Is Mediated By Macula Densa mentioning

confidence: 90%

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

Zhang¹,

Jin²,

Jiang³

et al. 2019

JASN

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“…RPE cells are activated by the breakdown of the outer blood-retinal barrier, and can undergo proliferation and migration and secrete extracellular matrix (ECM) molecules in vitreoretinal disorders, such as proliferative diabetic retinopathy (DR), proliferative vitreoretinopathy (PVR) and age-related macular degeneration (AMD) (1)(2)(3). RPE cells are known to contribute to inflammation and fibrosis in vitreoretinal disorders (4) and in the formation of fibrotic membranes (5).…”

Section: Introductionmentioning

confidence: 99%

High glucose-induced epithelial-mesenchymal transition contributes to the upregulation of fibrogenic factors in retinal pigment epithelial cells

Che

Zhou

Lan

et al. 2016

International Journal of Molecular Medicine

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It has been reported that epithelial-mesenchymal transition (EMT) mediates multiple physiological and pathological processes. However, the occurrence and the pathogenic role of high glucose-induced EMT in retinal pigment epithelial cells (RPE cells) is unknown. The aim of this study was to examine the effects of high glucose on EMT in RPE cells. Cultured RPE cells were exposed to 25 mM D-glucose. A vector encoding the Snail gene and siRNA targeting Snail (Snail siRNA) were transfected into the cells to induce the overexpression or silencing of Snail, respectively. AKT and extracellular signal-regulated kinase (ERK) inhibitors were used to block the activation of AKT and ERK, respectively. The levels of EMT markers, fibrogenic factors, phosphorylated ERK and phosphorylated AKT were determined by western blot analysis and immunofluorescence staining. Cell migration was evaluated by wound healing assay. Our results revealed that high glucose elevated the expression of the key EMT transcriptional factor, Snail, and that of other mesenchymal makers, and promoted cell migration. Moreover, the overexpression of Snail elevated the levels of fibronectin and connective tissue growth factor (CTGF), whereas the silencing of Snail decreased the expression of fibronectin and CTGF induced by high glucose in the cells. Mechanistically, the AKT inhibitor (AKT inhibitor IV) and ERK inhibitor (U0126) significantly decreased the expression of Snail, as well as the levels of fibronectin and CTGF which were induced by high glucose. On the whole, and to the best of our knowedge, the present study is the first to demonstrate the upregulation of mesenchymal markers in RPE cells induced by high glucose, and suggest that mesenchymal transition may be involved in the pathological processes of retinal diseases.

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“…It promotes in vitro invasion and migration of A549 lung cancer cells [31] and activates the PI3K/Akt pathway in hepatocellular carcinoma [41]. Fibronectin itself is induced through the PI3K/ Akt pathway in human retinal pigmental epithelial cells [42]. Concomitantly, phosphorylation of Akt was increased in our MMP9-silenced HSC-3 cells.…”

Section: Discussionmentioning

confidence: 75%

Matrix metalloproteinase 9 inhibits the motility of highly aggressive HSC-3 oral squamous cell carcinoma cells

Väyrynen

Åström

Nyberg

et al. 2019

Experimental Cell Research

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Pro-tumorigenic activities of matrix metalloproteinase (MMP) 9 have been linked to many cancers, but recently the tumour-suppressing role of MMP9 has also been elucidated. The multifaceted evidence on this subject prompted us to examine the role of MMP9 in the behaviour of oral tongue squamous cell carcinoma (OTSCC) cells. We used gelatinase-specific inhibitor, CTT2, and short hairpin (sh) RNA gene silencing to study the effects of MMP9 on proliferation, motility and invasion of an aggressive OTSCC cell line, HSC-3. We found that the migration and invasion of HSC-3 cells were increased by CTT2 and shRNA silencing of MMP9. Proliferation, in turn, was decreased by MMP9 inhibition. Furthermore, arresten-overexpressing HSC-3 cells expressed increased levels of MMP9, but exhibited decreased motility compared with controls. Interestingly, these cells restored their migratory capabilities by CTT2 inhibition of MMP9. Hence, although higher MMP9 expression could give rise to an increased tumour growth in vivo due to increased proliferation, in some circumstances, it may participate in yet unidentified molecular mechanisms that reduce the cell movement in OTSCC.

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The PI3K/Akt Signaling Pathway Mediates the High Glucose-Induced Expression of Extracellular Matrix Molecules in Human Retinal Pigment Epithelial Cells

Cited by 35 publications

References 27 publications

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

Macula Densa SGLT1-NOS1-Tubuloglomerular Feedback Pathway, a New Mechanism for Glomerular Hyperfiltration during Hyperglycemia

High glucose-induced epithelial-mesenchymal transition contributes to the upregulation of fibrogenic factors in retinal pigment epithelial cells

Matrix metalloproteinase 9 inhibits the motility of highly aggressive HSC-3 oral squamous cell carcinoma cells

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