High Glucose, High Insulin, and Their Combination Rapidly Induce Laminin-β1 Synthesis by Regulation of mRNA Translation in Renal Epithelial Cells

Mariappan, Meenalakshmi M.; Féliers, Denis; Mummidi, Srinivas; Choudhury, Goutam Ghosh; Kasinath, Balakuntalam S.

doi:10.2337/db05-1334

Cited by 72 publications

(100 citation statements)

References 52 publications

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“…48,49 Several studies have also suggested that mTOR activation has a crucial role in the pathogenesis of kidney hypertrophy and increase of matrix proteins in the GBM in diabetic nephropathy. 50,51 However, to our knowledge, there has been only one report on the role of mTOR activation in anti-GBM nephritis showing that pretreatment of rapamycin protected glomerular injury through affecting T-and B-cell activation. 52 However, the typical glomerular change in their animal model was severe mesangial expansion and not CGN.…”

Section: Discussionmentioning

confidence: 99%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. Immunohistochemistry and western blot analysis of glomeruli isolated from a rat model of CGN revealed that activation of mTORC1 preceded crescent formation in glomerular parietal epithelial cells (PECs) and podocytes. Daily treatment of rats with the mTOR inhibitor everolimus just after induction of CGN was not beneficial and instead led to increased cellular necrosis of PECs. However, daily treatment starting 7 days after the onset of CGN was beneficial and maintained intact glomeruli. Out of three forms of L-type neutral amino acid transporters (LAT1-LAT3) studied here, only LAT2 was found to be upregulated in the PECs and podocytes in advance of the crescent formation as well as in the crescent lesion itself. Cell culture study revealed that plasma membrane expression of LAT2 markedly stimulated mTORC1 signaling pathway, which was significantly abrogated by coexistence of LAT inhibitor. Finally, LAT inhibitor significantly abrogated development of crescent formation of CGN on day 7. Our data suggest that LAT2 may have a pivotal role in the pathogenesis of CGN by activating the mTORC1 pathway in the glomerular epithelial cells. Crescentic glomerulonephritis (CGN) is the most severe form of glomerulonephritis, and if untreated, progresses to endstage renal failure within days or weeks of diagnosis. Despite different etiologies and clinical manifestations among patients with CGN, there is a common glomerular pathology characterized by the disruption of glomerular basement membrane (GBM), followed by the flow of plasma proteins and inflammatory cells into the Bowman's space. 1 Several studies suggest that proliferating glomerular epithelial cells and accumulation of infiltrated macrophages are the main components of the cellular crescents. 2-6 Recent reports have further revealed that the cellular crescent lesions in CGN consist of podocytes in addition to glomerular parietal epithelial cells (PECs) and macrophages. [7][8][9] It is increasingly evident that proinflammatory cytokines and growth hormones released by proliferating cells in the glomerulus are involved in the pathogenesis of crescent formation. [10][11][12][13] These factors stimulate the p38 mitogen-activated protein kinase (MAPK) pathway, resulting in the production of inflammatory mediators. [14][15][16] The involvement of the MAPK pathway in the pathogenesis of CGN was first reported by Bokemeyer et al, 17 who demonstrated a rapid and sustained activation of extracellular signal-regulated kinase in the glomeruli isolated from rat model of anti-GBM nephritis. A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling path...

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Section: Discussionmentioning

confidence: 99%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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“…Acute Effects of Ang II on Fibronectin Synthesis and Deposition-It has been proposed that recurrent acute stimulation of extracellular matrix protein synthesis by renal cells participates in the significant expansion of matrix leading to fibrosis in kidney disease (52). This observation prompted us to investigate the effect of short term exposure of MCs to Ang II on the fibronectin synthesis and deposition.…”

Section: Involvement Of Src In Ang Ii-induced Pdk-1 Tyrosinementioning

confidence: 99%

Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II

Block

Eid

Griendling

et al. 2008

Journal of Biological Chemistry

125

133

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Activation of glomerular mesangial cells (MCs) by angiotensin II (Ang II) leads to hypertrophy and extracellular matrix accumulation. Here, we demonstrate that, in MCs, Ang II induces an increase in PDK-1 (3-phosphoinositide-dependent protein kinase-1) kinase activity that required its phosphorylation on tyrosine 9 and 373/376. Introduction into the cells of PDK-1, mutated on these tyrosine residues or kinase-inactive, attenuates Ang II-induced hypertrophy and fibronectin accumulation. Ang II-mediated PDK-1 activation and tyrosine phosphorylation (total and on residues 9 and 373/376) are inhibited in cells transfected with small interfering RNA for Src, indicating that Src is upstream of PDK-1. In cells expressing oxidationresistant Src mutant C487A, Ang II-induced hypertrophy and fibronectin expression are prevented, suggesting that the pathway is redox-sensitive. Ang II also up-regulates Nox4 protein, and siNox4 abrogates the Ang II-induced increase in intracellular reactive oxygen species (ROS) generation. Small interfering RNA for Nox4 also inhibits Ang II-induced activation of Src and PDK-1 tyrosine phosphorylation (total and on residues 9 and 373/376), demonstrating that Nox4 functions upstream of Src and PDK-1. Importantly, inhibition of Nox4, Src, or PDK-1 prevents the stimulatory effect of Ang II on fibronectin accumulation and cell hypertrophy. This work provides the first evidence that Nox4-derived ROS are responsible for Ang II-induced PDK-1 tyrosine phosphorylation and activation through stimulation of Src. Importantly, this pathway contributes to Ang IIinduced MC hypertrophy and fibronectin accumulation. These data shed light on molecular processes underlying the oxidative signaling cascade engaged by Ang II and identify potential targets for intervention to prevent renal hypertrophy and fibrosis.Cellular hypertrophy and extracellular matrix accumulation in glomeruli contributes to the pathogenesis of glomerulosclerosis in fibrotic renal diseases (1-5). The octapeptide hormone angiotensin II (Ang II) 2 is the dominant renin-angiotensin system effector (5-7) and is implicated in the pathogenesis of fibrosis of the glomerular microvascular bed. Up-regulation of the renin-angiotensin system plays a key role in the initiation and the progression of glomerular injury via induction of hypertrophy and extracellular matrix expansion in glomerular mesangial cells (MCs) (6 -13).Ang II-induced oxidative stress has emerged as a critical pathogenic factor in the development of renal and vascular diseases (13-16). NAD(P)H oxidases of the Nox family are major sources of reactive oxygen species (ROS) in many nonphagocytic cells, including renal cells (17-21). The Nox proteins correspond to homologues of gp91 phox (or Nox2), the catalytic moiety found in phagocytes (17,18). Seven members of the Nox family have been identified in the human genome: Nox1 to -5 and the dual oxidases Duox1 and -2 (17, 18, 22). The isoform Nox4 (NAD(P)H oxidase 4) is abundant in the vascular system and kidney cortex (16, 17, 19 -22). We ...

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“…To further substantiate our results, we employed a loss-of-function strategy. We used an adenovirus vector expressing a dominant negative FoxO1 that inhibits FoxO1-dependent transcription ( FoxO1 Regulates High Glucose-induced mTORC1 ActivationWe have shown recently that high glucose activates mTORC1 in an Akt kinase-dependent manner (5,8,11,27). This activation of mTORC1 occurs via Akt-dependent phosphorylation of PRAS40, which is a component and negative regulator of mTORC1.…”

Section: High Glucose-induced Foxo1 Phosphorylation Regulates Aktmentioning

confidence: 99%

“…We and others have shown a significant role of this kinase cascade in inducing renal hypertrophy and matrix expansion in diabetic animals and in cultured mesangial and proximal tubular epithelial cells (5)(6)(7)(8)(9)(10). Our recent observation that hyperglycemia reduces the tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome 10), which acts as a lipid phosphatase to dephosphorylate the PI 3,4,5-trisphosphate, also contributes to the hyperactivation of Akt in diabetic renal glomeruli and in mesangial cells, therefore providing an additional mechanism of Akt activation in diabetic kidney disease (7,11).…”

mentioning

confidence: 99%

“…Our recent observation that hyperglycemia reduces the tumor suppressor protein PTEN (phosphatase and tensin homolog deleted on chromosome 10), which acts as a lipid phosphatase to dephosphorylate the PI 3,4,5-trisphosphate, also contributes to the hyperactivation of Akt in diabetic renal glomeruli and in mesangial cells, therefore providing an additional mechanism of Akt activation in diabetic kidney disease (7,11). Subsequently, the phosphor-ylation of key substrates such as PRAS40 and tuberin by Akt activates the mechanistic target of rapamycin complex 1 (mTORC1) to induce hypertrophy and matrix protein expression, two pathologic features of diabetic nephropathy (5,8,11).…”

mentioning

confidence: 99%

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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

Das

Ghosh‐Choudhury

Dey

et al. 2014

Journal of Biological Chemistry

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High Glucose, High Insulin, and Their Combination Rapidly Induce Laminin-β1 Synthesis by Regulation of mRNA Translation in Renal Epithelial Cells

Cited by 72 publications

References 52 publications

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Nox4 NAD(P)H Oxidase Mediates Src-dependent Tyrosine Phosphorylation of PDK-1 in Response to Angiotensin II

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

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