Angiotensin II inhibits insulin-stimulated phosphorylation of eukaryotic initiation factor 4E-binding protein-1 in proximal tubular epithelial cells

2001 ◽  
Vol 360 (1) ◽  
pp. 87-95 ◽  
Author(s):  
Duraisamy SENTHIL ◽  
Jennifer L. FAULKNER ◽  
Goutam GHOSH CHOUDHURY ◽  
Hanna E. ABBOUD ◽  
Balakuntalam S. KASINATH
Keyword(s):  
Protein Synthesis ◽  
Angiotensin Ii ◽  
Insulin Signalling ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Tubular Epithelial Cells ◽  
Eukaryotic Initiation Factor 4E ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Stimulation Of

Interaction between angiotensin II, which binds a G-protein-coupled receptor, and insulin, a ligand for receptor tyrosine kinase, was examined in renal proximal tubular epithelial cells. Augmented protein translation by insulin involves activation of eukaryotic initiation factor 4E (eIF4E) which follows the release of the factor from a heterodimeric complex by phosphorylation of its binding protein, 4E-BP1. Angiotensin II (1nM) or insulin (1nM) individually stimulated 4E-BP1 phosphorylation. However, pre-incubation with angiotensin II abrogated insulin-induced phosphorylation of 4E-BP1, resulting in persistent binding to eIF4E. Although angiotensin II and insulin individually activated phosphoinositide 3-kinase and extracellular signal-regulated kinase (ERK)-1/−2-type mitogen-activated protein (MAP) kinase, pre-incubation with angiotensin II abolished insulin-induced stimulation of these kinases, suggesting more proximal events in insulin signalling may be intercepted. Pretreatment with angiotensin II markedly inhibited insulin-stimulated tyrosine phosphorylation of insulin-receptor β-chain and insulin-receptor substrate 1. Losartan prevented angiotensin II inhibition of insulin-induced ERK-1/−2-type MAP kinase activation and 4E-BP1 phosphorylation, suggesting mediation of the effect of angiotensin II by its type 1 receptor. Insulin-stimulated de novo protein synthesis was also abolished by pre-incubation with angiotensin II. These data show that angiotensin II inhibits 4E-BP1 phosphorylation and stimulation of protein synthesis induced by insulin by interfering with proximal events in insulin signalling. Our data provide a mechanistic basis for insulin insensitivity induced by angiotensin II.

Regulation of protein synthesis by IGF-I in proximal tubular epithelial cells

2002 ◽  
Vol 283 (6) ◽  
pp. F1226-F1236 ◽  
Author(s):  
Duraisamy Senthil ◽  
Goutam Ghosh Choudhury ◽  
Hanna E. Abboud ◽  
Nahum Sonenberg ◽  
Balakuntalam S. Kasinath
Keyword(s):  
Protein Synthesis ◽  
Epithelial Cells ◽  
Protein Translation ◽  
Initiation Factor ◽  
Tubular Epithelial Cells ◽  
Renal Hypertrophy ◽  
Eukaryotic Initiation Factor 4E ◽  
Igf I ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular

Protein synthesis is required for renal hypertrophy, and proximal tubular epithelial cells are an important cell type involved in this process. We examined IGF-I regulation of protein synthesis in murine proximal tubular epithelial (MCT) cells. We focused on initial events in protein translation and the signaling events involved. Translation of capped mRNAs is under the control of eukaryotic initiation factor 4E (eIF4E). In the resting cell, eIF4E is normally kept in an inactive state by binding to 4E-BP1, its binding protein. Phosphorylation of 4E-BP1 results in dissociation of the eIF4E-4E-BP1 complex allowing eIF4E to initiate peptide synthesis. IGF-I stimulated protein synthesis, augmented phosphorylation of 4E-BP1 and promoted the dissociation of eIF4E from 4E-BP1. IGF-I stimulated the activities of phosphatidylinositol (PI) 3-kinase, Akt, and ERK1/2-type MAPK in MCT cells. IGF-I-induced phosphorylation of 4E-BP1, dissociation of the 4E-BP1-eIF4E complex, and increase in protein synthesis required activation of both PI 3-kinase and ERK pathways. Furthermore, ERK activation by IGF-I was also PI 3-kinase dependent. Transfection with the Thr37,46→Ala37,46mutant of 4E-BP1 showed that phosphorylation of Thr37,46residues was required for IGF-I induction of protein synthesis in MCT cells. Our observations reveal the importance of initial events in protein translation in IGF-I-induced protein synthesis in MCT cells and identify the regulatory signaling pathways involved.

scholarly journals Phosphorylation of eukaryotic initiation factor 4E (eIF4E) at Ser209 is not required for protein synthesis in vitro and in vivo

2001 ◽  
Vol 268 (20) ◽  
pp. 5375-5385 ◽  
Author(s):  
Linda McKendrick ◽  
Simon J. Morley ◽  
Virginia M. Pain ◽  
Rosemary Jagus ◽  
Bhavesh Joshi
Keyword(s):  
Protein Synthesis ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Eukaryotic Initiation Factor 4E

scholarly journals Interleukin 2 mediates stimulation of complement C3 biosynthesis in human proximal tubular epithelial cells.

1991 ◽  
Vol 88 (2) ◽  
pp. 379-384 ◽  
Author(s):  
R A Brooimans ◽  
A P Stegmann ◽  
W T van Dorp ◽  
A A van der Ark ◽  
F J van der Woude ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Interleukin 2 ◽  
Complement C3 ◽  
Tubular Epithelial Cells ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Stimulation Of

ANG II activates effectors of mTOR via PI3-K signaling in human coronary smooth muscle cells

2004 ◽  
Vol 287 (3) ◽  
pp. H1232-H1238 ◽  
Author(s):  
Sassan Hafizi ◽  
Xuemin Wang ◽  
Adrian H. Chester ◽  
Magdi H. Yacoub ◽  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Signaling Pathway ◽  
Initiation Factor ◽  
Ang Ii ◽  
Eukaryotic Initiation Factor ◽  
Mtor Signaling Pathway ◽  
Phosphatidylinositol 3 Kinase ◽  
Eukaryotic Initiation Factor 4E

We have previously shown that the vasoconstrictive peptide angiotensin II (ANG II) is a hypertrophic agent for human coronary artery smooth muscle cells (cSMCs), which suggests that it plays a role in vascular wall thickening. The present study investigated the intracellular signal transduction pathways involved in the growth response of cSMCs to ANG II. The stimulation of protein synthesis by ANG II in cSMCs was blocked by the immunosuppressant rapamycin, which is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway that includes the 70-kDa S6 kinase (p70S6k) and plays a key role in cell growth. The inhibitory effect of rapamycin was reversed by a molar excess of FK506; this indicates that both agents act through the common 12-kDa immunophilin FK506-binding protein. ANG II caused a rapid and sustained activation of p70S6k activity that paralleled its phosphorylation, and both processes were blocked by rapamycin. In addition, both of the phosphatidylinositol 3-kinase inhibitors wortmannin and LY-294002 abolished the ANG II-induced increase in protein synthesis, and wortmannin also blocked p70S6k phosphorylation. Furthermore, ANG II triggered dissociation of the translation initiation factor, eukaryotic initiation factor-4E, from its regulatory binding protein 4E-BP1, which was also inhibited by rapamycin and wortmannin. In conclusion, we have shown that ANG II activates components of the rapamycin-sensitive mTOR signaling pathway in human cSMCs and involves activation of phosphatidylinositol 3-kinase, p70S6k, and eukaryotic initiation factor-4E, which leads to activation of protein synthesis. These signaling mechanisms may mediate the growth-promoting effect of ANG II in human cSMCs.

Defective D1-like receptor-mediated inhibition of the Cl−/HCO3− exchanger in immortalized SHR proximal tubular epithelial cells

2004 ◽  
Vol 286 (6) ◽  
pp. F1120-F1126 ◽  
Author(s):  
Rui Pedrosa ◽  
Pedro A. Jose ◽  
P. Soares-da-Silva
Keyword(s):  
Epithelial Cells ◽  
Apical Cell ◽  
Skf 38393 ◽  
Tubular Epithelial Cells ◽  
Receptor Stimulation ◽  
Anion Transporter ◽  
Proximal Tubular Epithelial Cells ◽  
Proximal Tubular ◽  
Wistar Kyoto ◽  
Stimulation Of

The sensitivity of the Cl−/HCO3− exchanger to dopamine D1- and D2-like receptor stimulation in immortalized renal proximal tubular epithelial cells from the spontaneous hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) was examined. The activity of the Cl−/HCO3− exchanger (in pH U/s) in SHR cells (0.00191) was greater than in WKY cells (0.00126). The activity of Cl−/HCO3− exchanger was exclusively observed at the apical cell side and probably occurs through the SLC26A6 anion transporter that is expressed in both WKY and SHR cells. Stimulation of D1-like receptors with SKF-38393 markedly attenuated the HCO3−-dependent intracellular pH recovery in WKY cells but not in SHR cells. Stimulation of D2-like receptors with quinerolane did not alter Cl−/HCO3− exchanger activity in both WKY and SHR cells. The selective D1-like receptor antagonist SKF-83566 prevented the effect of SKF-38393. Both WKY and SHR cells responded to dibutyryl-cAMP (DBcAMP) with inhibition of the Cl−/HCO3− exchanger, and downregulation of PKA (overnight exposure to DBcAMP) abolished the inhibitory effect of both DBcAMP and SKF-38393 in WKY cells. Both SHR and WKY cells responded to forskolin with increases in the formation of cAMP. However, only WKY responded to SKF-38393 with increases in the formation of cAMP that was prevented by SKF-83566. It is concluded that WKY cells respond to D1-like dopamine receptor stimulation with inhibition of the apical Cl−/HCO3− (SLC26A6) exchanger and SHR cells have a defective D1-like dopamine response.

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