Deacetylation of S6 kinase promotes high glucose–induced glomerular mesangial cell hypertrophy and matrix protein accumulation

Aberrant expression of microRNAs (miRs) contributes to diabetic renal complications, including renal hypertrophy and matrix protein accumulation. Reduced expression of phosphatase and tensin homolog (PTEN) by hyperglycemia contributes to these processes. We considered involvement of miR in the downregulation of PTEN. In the renal cortex of type 1 diabetic mice, we detected increased expression of miR-214 in association with decreased levels of PTEN and enhanced Akt phosphorylation and fibronectin expression. Mesangial and proximal tubular epithelial cells exposed to high glucose showed augmented expression of miR-214. Mutagenesis studies using 3′-UTR of PTEN in a reporter construct revealed PTEN as a direct target of miR-214, which controls its expression in both of these cells. Overexpression of miR-214 decreased the levels of PTEN and increased Akt activity similar to high glucose and lead to phosphorylation of its substrates glycogen synthase kinase-3β, PRAS40, and tuberin. In contrast, quenching of miR-214 inhibited high-glucose-induced Akt activation and its substrate phosphorylation; these changes were reversed by small interfering RNAs against PTEN. Importantly, respective expression of miR-214 or anti-miR-214 increased or decreased the mammalian target of rapamycin complex 1 (mTORC1) activity induced by high glucose. Furthermore, mTORC1 activity was controlled by miR-214-targeted PTEN via Akt activation. In addition, neutralization of high-glucose-stimulated miR-214 expression significantly inhibited cell hypertrophy and expression of the matrix protein fibronectin. Finally, the anti-miR-214-induced inhibition of these processes was reversed by the expression of constitutively active Akt kinase and hyperactive mTORC1. These results uncover a significant role of miR-214 in the activation of mTORC1 that contributes to high-glucose-induced mesangial and proximal tubular cell hypertrophy and fibronectin expression.

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microRNA-181a downregulates deptor for TGFβ-induced glomerular mesangial cell hypertrophy and matrix protein expression

Experimental Cell Research ◽

10.1016/j.yexcr.2018.01.021 ◽

2018 ◽

Vol 364 (1) ◽

pp. 5-15 ◽

Cited By ~ 6

Author(s):

Soumya Maity ◽

Amit Bera ◽

Nandini Ghosh-Choudhury ◽

Falguni Das ◽

Balakuntalam S. Kasinath ◽

...

Keyword(s):

Protein Expression ◽

Matrix Protein ◽

Mesangial Cell ◽

Glomerular Mesangial Cell ◽

Cell Hypertrophy

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High Glucose Forces a Positive Feedback Loop Connecting Akt Kinase and FoxO1 Transcription Factor to Activate mTORC1 Kinase for Mesangial Cell Hypertrophy and Matrix Protein Expression

Journal of Biological Chemistry ◽

10.1074/jbc.m114.605196 ◽

2014 ◽

Vol 289 (47) ◽

pp. 32703-32716 ◽

Cited By ~ 24

Author(s):

Falguni Das ◽

Nandini Ghosh-Choudhury ◽

Nirmalya Dey ◽

Amit Bera ◽

Meenalakshmi M. Mariappan ◽

...

Keyword(s):

Transcription Factor ◽

Protein Expression ◽

Positive Feedback ◽

High Glucose ◽

Feedback Loop ◽

Matrix Protein ◽

Mesangial Cell ◽

Akt Kinase ◽

Positive Feedback Loop ◽

Cell Hypertrophy

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Tyrosines-740/751 of PDGFRβ contribute to the activation of Akt/Hif1α/TGFβ nexus to drive high glucose-induced glomerular mesangial cell hypertrophy

Cellular Signalling ◽

10.1016/j.cellsig.2017.09.017 ◽

2018 ◽

Vol 42 ◽

pp. 44-53 ◽

Cited By ~ 3

Author(s):

Falguni Das ◽

Nandini Ghosh-Choudhury ◽

Balakuntalam S. Kasinath ◽

Goutam Ghosh Choudhury

Keyword(s):

High Glucose ◽

Mesangial Cell ◽

Glomerular Mesangial Cell ◽

Cell Hypertrophy

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Urotensin II-induced store-operated Ca2+ entry contributes to glomerular mesangial cell proliferation and extracellular matrix protein production under high glucose conditions

Scientific Reports ◽

10.1038/s41598-017-18143-x ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Hitesh Soni ◽

Adebowale Adebiyi

Keyword(s):

Extracellular Matrix ◽

Cell Proliferation ◽

High Glucose ◽

Protein Production ◽

Matrix Protein ◽

Mesangial Cell ◽

Extracellular Matrix Protein ◽

Urotensin Ii ◽

Glomerular Mesangial Cell ◽

Mesangial Cell Proliferation

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High glucose-stimulated enhancer of zeste homolog-2 (EZH2) forces suppression of deptor to cause glomerular mesangial cell pathology

Cellular Signalling ◽

10.1016/j.cellsig.2021.110072 ◽

2021 ◽

pp. 110072

Author(s):

Falguni Das ◽

Amit Bera ◽

Nandini Ghosh-Choudhury ◽

Kavitha Sataranatarajan ◽

Amrita Kamat ◽

...

Keyword(s):

High Glucose ◽

Mesangial Cell ◽

Glomerular Mesangial Cell ◽

Enhancer Of Zeste

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LncRNA NEAT1 Promotes High Glucose-Induced Mesangial Cell Hypertrophy by Targeting miR-222-3p/CDKN1B Axis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.627827 ◽

2021 ◽

Vol 7 ◽

Author(s):

Lin Liao ◽

Jie Chen ◽

Chuanfu Zhang ◽

Yue Guo ◽

Weiwei Liu ◽

...

Keyword(s):

High Glucose ◽

Noncoding Rna ◽

Mesangial Cell ◽

Mesangial Cells ◽

Morphological Alteration ◽

Glomerular Hypertrophy ◽

Cell Hypertrophy ◽

Rna Immunoprecipitation ◽

Lncrna Neat1

Glomerular hypertrophy is an early morphological alteration in diabetic nephropathy. Cyclin-Dependent Kinases have been shown to be required for high glucose (HG)-induced hypertrophy; however, the upstream regulators of CDKN1B in glomerular hypertrophy remain unclear. Herein we describe a novel pathway in which Long noncoding RNA (lncRNA) NEAT1 regulates the progression of mesangial cell hypertrophy via a competing endogenous RNA (ceRNA) mechanism. Real-time PCR was performed to detect the relative NEAT1 and miR-222-3p expressions and further confirmed the relationship between NEAT1 and miR-222-3p. Cell cycle was evaluated by flow cytometry. The related mechanisms were explored by Western blot, RNA immunoprecipitation and chromatin immunoprecipitation assay. We show that NEAT1 forms double stranded RNA (dsRNA) with miR-222-3p, thus limiting miR-222-3p’s binding with CDKN1B. This release of CDKN1B mRNA leads to elevated CDKN1B protein expression, resulting in hypertrophy. In addition, we demonstrated that STAT3 which is activated by HG induces the transcription of NEAT1 by binding to its promoter. Our findings underscore an unexpected role of lncRNAs on gene regulation and introduce a new mode of proliferation regulation in mesangial cells.

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Hexosamines and TGF-β1 use similar signaling pathways to mediate matrix protein synthesis in mesangial cells

AJP Renal Physiology ◽

10.1152/ajprenal.00007.2003 ◽

2004 ◽

Vol 286 (2) ◽

pp. F409-F416 ◽

Cited By ~ 26

Author(s):

Lalit P. Singh ◽

Kenneith Green ◽

Michelle Alexander ◽

Shira Bassly ◽

Errol D. Crook

Keyword(s):

High Glucose ◽

Matrix Protein ◽

Transforming Growth Factor ◽

Cell Function ◽

Mesangial Cells ◽

Rat Kidney ◽

Protein Accumulation ◽

Western Blots ◽

Matrix Production ◽

Mes Cells

Hyperglycemia-induced alterations in mesangial (MES) cell function and extracellular matrix (ECM) protein accumulation are seen in diabetic glomerulopathy. Transforming growth factor-β1 (TGF-β1) mediates high-glucose-induced matrix production in the kidney. Recent studies demonstrated that some of the effects of high glucose on cellular metabolism are mediated by the hexosamine biosynthesis pathway (HBP) in which fructose-6-phosphate is converted to glucosamine (GlcN) 6-phosphate. We previously showed that the high-glucose-mediated fibronectin and laminin synthesis in MES cells is mediated by the HBP and that GlcN is more potent than glucose in inducing TGF-β1 promoter luciferase activity. In this study, we investigated the hypothesis that the effects of glucose on MES matrix production occur via hexosamine regulation of TGF-β1. Culturing simian virus (SV)-40-transformed rat kidney MES cells in 25 mM glucose (HG) for 48 h increases cellular fibronectin and laminin levels about twofold on Western blots compared with low glucose (5 mM). GlcN (1.5 mM) or TGF-β1 (2.5-5 ng/ml) for 24-48 h also increases ECM synthesis. However, the effects of HG or GlcN with TGF-β1 are not additive. The presence of anti-TGF-β1 antibodies (20 μg/ml) blocks both TGF-β1- and GlcN-induced fibronectin synthesis. TGF-β1 increased ECM levels via PKA (laminin and fibronectin) and PKC (fibronectin) pathways. Similarly, TGF-β1 and hexosamines led to nonadditive increases in phosphorylation of the cAMP responsive element binding transcription factor. These results suggest that the effects of excess glucose on MES ECM synthesis occur via HBP-mediated regulation of TGF-β1.

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