Akt/PKB regulates laminin and collagen IV isotypes of the basement membrane

Li, Xiaofeng; Talts, Ulrika; Talts, Jan F.; Arman, Esther; Ekblom, Peter; Lonai, Peter

doi:10.1073/pnas.251547198

Cited by 62 publications

(46 citation statements)

References 40 publications

(56 reference statements)

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“…Overexpression of constitutively active Akt also increased collagen I production in hepatic stellate cells (18) and collagen IV production in embryoid bodies (17). The accumulation of extracellular matrix, including collagen I, is a hallmark of glomerulosclerosis secondary to increased intraglomerular pressure (2,38).…”

Section: Akt Activation Mediates Strain-induced Collagen Production Imentioning

confidence: 99%

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Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Krepinsky¹,

Li²,

Chang³

et al. 2005

Journal of the American Society of Nephrology

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Increased glomerular hydrostatic pressure is an important determinant of glomerulosclerosis and can be modeled by in vitro exposure of mesangial cells to cyclic mechanical strain. Stretched mesangial cells increase extracellular matrix protein production, the hallmark of glomerulosclerosis. Recent data indicate that the serine/threonine kinase Akt may be involved in matrix modulation. Thus, Akt activation and matrix synthesis in stretched mesangial cells were studied. Exposure of mesangial cells to 1 Hz cyclic strain led to prompt Akt activation, which was biphasic to 24 h. Activation was dependent on signaling through phosphatidylinositol-3-kinase and required EGF receptor transactivation. Inhibition of signaling through the PDGF receptor, Src kinase, or cytoskeletal disruption failed to prevent strain-induced Akt activation. Collagen type 1A1 transcript expression, promoter activation, and protein secretion were increased by stretch at 24 h and were dependent on phosphatidylinositol-3 kinase. Overexpression of dominant-negative Akt inhibited strain-induced collagen 1A1 production. Conversely, overexpression of constitutively active Akt led to increased collagen 1A1 upregulation and secretion. Finally, Akt activation was observed in the glomeruli of remnant rat kidneys, a model marked by increased intraglomerular pressure. The authors conclude that mechanical strain induces Akt activation in mesangial cells through a mechanism requiring phosphatidylinositol-3-kinase and EGF receptor transactivation. Type 1 collagen production is dependent on Akt and can be induced by Akt overexpression. Akt activation is observed in remnant kidneys in vivo. Thus, the role of Akt in progression of chronic hemodynamic glomerular disease is worthy of further exploration.

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Section: Akt Activation Mediates Strain-induced Collagen Production Imentioning

confidence: 99%

“…Constitutively active Akt or PI3K induced laminin and collagen IV synthesis in embryoid bodies and Chinese hamster ovary cells (17). PI3K was shown to be important in basal production of collagen 1A1 transcript levels in hepatic stellate cells and human lung fibroblasts (18,19).…”

mentioning

confidence: 98%

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Krepinsky¹,

Li²,

Chang³

et al. 2005

Journal of the American Society of Nephrology

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“…2B). To further determine whether FGF signaling through the PI3K pathway is required for maintaining the undifferentiated status of hESC, we assessed the differentiation of hESCs which were treated with a selective PI3K inhibitor, LY294002 [13]. Regardless of the presence or absence of FGF2 in the media, PI3K inhibition significantly reduced the AP activity (a marker of the undifferentiated state) (Fig.…”

Section: R E T R a C T E Dmentioning

confidence: 99%

RETRACTED: Contribution of the PI3K/Akt/PKB signal pathway to maintenance of self‐renewal in human embryonic stem cells

Kim

Cheon

Yoo³

et al. 2004

FEBS Letters

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Although basic fibroblast growth factor (FGF2) is generally included in the media for maintenance of human embryonic stem cells (hESCs), the action of FGF2 in these cells has not been well defined. Here, we determined the roles of FGF2 in maintaining hESC self-renewal. Withdrawal of FGF2 from the media led to acquisition of typical differentiated characteristics in hESCs. In the presence of FGF2, which is normally required for proliferation in an undifferentiated state, inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/PKB signal stimulated differentiation and attenuated the expression of extracellular matrix (ECM) molecules. We suggest that FGF2 maintains hESC self-renewal by supporting stable expression of ECM molecules through activation of the PI3K/Akt/PKB pathway.

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“…This is followed by phosphorylation at serine 473 by a yet-to-be identified mechanism (17). Growing evidence indicates that ANG II/AT-1R signaling induces a crosstalk to the PI3K/Akt pathway (18 -21), and a few studies have shown that these changes in PI3K/Akt activities demonstrated altered phenotypes in collagen synthesis of various types of cells, including MCs (22)(23)(24)(25). These findings suggested that ANG II/AT-1R signaling is implicated in hypersynthesis of collagens in MCs through a crosstalk with the PI3K/Akt signaling pathway and is involved in the development and progression of various kinds of glomerular diseases.…”

mentioning

confidence: 99%

A Novel Phosphoinositide 3-Kinase-dependent Pathway for Angiotensin II/AT-1 Receptor-mediated Induction of Collagen Synthesis in MES-13 Mesangial Cells

Yano

Suzuki

Endoh

et al. 2007

Journal of Biological Chemistry

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Chronic activation of the angiotensin II (ANG II) type 1 receptor (AT-1R) is critical in the development of chronic kidney disease. ANG II activates mesangial cells (MCs) and stimulates the synthesis of extracellular matrix components. To determine the molecular mechanisms underlying the induction of MC collagen, a mouse mesangial cell line MES-13 was employed. ANG II treatment induced an increase in collagen synthesis, which was abrogated by cotreatment with losartan (an AT-1R antagonist), wortmannin (a phosphoinositide 3-kinase (PI3K) inhibitor), an Akt inhibitor, and stable transfection of dominant negative-Akt1. ANG II induced a significant increase in PI3K activity, which was abolished by co-treatment with losartan or 2,5-dideoxyadenosine (2,5-DOA, an adenylyl cyclase inhibitor) but not by PD123319 (an AT-2R antagonist) or H89 (a protein kinase A (PKA) inhibitor). The Epac (exchange protein directly activated by cAMP)-specific cAMP analog, 8-pHPT-2-O-MecAMP, significantly increased PI3K activity, whereas a PKAspecific analog, 6-benzoyladenosine-cAMP, showed no effect. The ANG II-induced increase in PI3K activity was also blocked by co-treatment with PP2, an Src inhibitor, or AG1478, an epidermal growth factor receptor (EGFR) antagonist. ANG II induced phosphorylation of Akt and p70S6K and EGFR, which was abrogated by knockdown of c-Src by small interference RNA. Knockdown of Src also effectively abolished ANG II-induced collagen synthesis. Conversely, stable transfection of a constitutively active Src mutant enhanced basal PI3K activity and collagen production, which was abrogated by AG1478 but not by 2,5-DOA. Moreover, acute treatment with ANG II significantly increased Src activity, which was abrogated with co-treatment of 2,5-DOA. Taken together, these results suggest that ANG II induces collagen synthesis in MCs by activating the ANG II/AT-1R-EGFR-PI3K pathway. This transactivation is dependent on cAMP/Epac but not on PKA. Src kinase plays a pivotal role in this signaling pathway between cAMP and EGFR. This is the first demonstration that an AT1R-PI3K/ Akt crosstalk, along with transactivation of EGFR, mediates ANG II-induced collagen synthesis in MCs.Clinical and experimental studies have identified the reninangiotensin system as a key factor in development and progression of glomerular diseases (1-3). A chronically enhanced effect of the renin-angiotensin system is a central event in the development of proliferative and sclerosing changes in the glomeruli. The octapeptide hormone angiotensin II (ANG II), 2 the major renin-angiotensin system effector, activates mesangial cells (MCs) and increases the synthesis of extracellular matrix components, including collagens, which is a hallmark of the glomerular diseases (4, 5). The physiological functions of ANG II are mediated by at least two structurally and pharmacologically distinct seven-transmembrane helices G protein-coupled receptors (GPCRs), ANG II type 1 and 2 receptors (AT-1R and AT-2R). Glomerular cells, including MCs, express primarily the AT-1R, ...

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Akt/PKB regulates laminin and collagen IV isotypes of the basement membrane

Cited by 62 publications

References 40 publications

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

RETRACTED: Contribution of the PI3K/Akt/PKB signal pathway to maintenance of self‐renewal in human embryonic stem cells

A Novel Phosphoinositide 3-Kinase-dependent Pathway for Angiotensin II/AT-1 Receptor-mediated Induction of Collagen Synthesis in MES-13 Mesangial Cells

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