Synthesis and release of insulinlike growth factor I by mesangial cells in culture

1988 ◽  
Vol 255 (6) ◽  
pp. F1214-F1219 ◽  
Author(s):  
F. G. Conti ◽  
L. J. Striker ◽  
S. J. Elliot ◽  
D. Andreani ◽  
G. E. Striker
Keyword(s):  
Cell Proliferation ◽  
Growth Factor ◽  
Culture Medium ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Glomerular Mesangial Cells ◽  
Factor I ◽  
Cells In Culture ◽  
Igf I ◽  
Insulinlike Growth Factor I

Mesangial cell proliferation is a common hallmark of many glomerular diseases. The exact mechanisms inducing cell proliferation in glomerulosclerosis are not completely understood, and it remains to be determined whether growth factors play a role in this process. Insulinlike growth factor I (IGF I) has been shown to be synthesized in the kidney, and glomerular mesangial cells have receptors for and exhibit mitogenic response to IGF I. We found that mouse glomerular mesangial cells in culture synthesized and released into the culture medium a molecule with immunological and biological features of IGF I. This molecule specifically bound to mesangial cell IGF I receptors; high-pressure liquid chromatographic analysis provided further evidence of its similarity to human recombinant IGF I. Mesangial cells released into the culture medium 6 ng/10(6) cells of IGF I-like material per 24 h in a time-dependent and actinomycin-D inhibitable fashion. These data suggest that IGF I might be locally released by mesangial cells in the glomerulus and act in an autocrine and paracrine fashion.

Bimodal effects of platelet-derived growth factor on rat mesangial cell proliferation and death, and the role of lysophosphatidic acid in cell survival

2001 ◽  
Vol 101 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Chiyoko N. INOUE ◽  
Isao NAGANO ◽  
Ryo ICHINOHASAMA ◽  
Natsumi ASATO ◽  
Yoshiaki KONDO ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Growth Factor ◽  
Lysophosphatidic Acid ◽  
Culture Medium ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Platelet Derived Growth Factor ◽  
P53 Expression ◽  
Mesangial Cell Proliferation

Although mesangial cell death has been shown to be correlated with mesangial cell mitosis in vivo, little is known about how these two apparently opposite events are regulated. We show that the addition of platelet-derived growth factor (PDGF; 10–50 ng/ml) to primary cultured rat mesangial cells for 24 h caused continuous proliferation along with simultaneous cell death. This process was accompanied by the fragmentation of DNA into nucleosomal oligomers, the development of apoptotic morphological changes in the nucleus, and increased expression of p53. Accumulation of lactate dehydrogenase (LDH) was also observed in the culture medium, suggesting that both apoptosis and necrosis are involved in the cell death mechanisms observed. We also observed that addition of 30 µM lysophosphatidic acid (LPA) to the culture medium greatly suppressed PDGF-induced cell death, leading to synergistically enhanced mesangial cell proliferation. DNA fragmentation, p53 expression and LDH release were all suppressed by LPA. We suggest that PDGF is a bifunctional molecule in mesangial cells that evokes both cell proliferation and cell death simultaneously, whereas LPA is a survival factor. We speculate that PDGF and LPA may play important roles in the progression or exacerbation of proliferative glomerulonephritis.

Insulin-like growth factor I (IGF-I) stimulates glucose and amino acid uptake in cultured glomerular mesangial cells

1991 ◽  
Vol 5 (2-3) ◽  
pp. 184-185 ◽  
Author(s):  
Masaki Togawa ◽  
Ryuichi Kikkawa ◽  
Masakazu Haneda ◽  
Daisuke Koya ◽  
Naoki Horide ◽  
...  
Keyword(s):  
Amino Acid ◽  
Growth Factor ◽  
Mesangial Cells ◽  
Amino Acid Uptake ◽  
Acid Uptake ◽  
Insulin Like Growth Factor ◽  
Glomerular Mesangial Cells ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

scholarly journals Insulin-like Growth Factor I (IGF-I) Induces Unique Effects in the Cytoskeleton of Cultured Rat Glomerular Mesangial Cells

1997 ◽  
Vol 45 (4) ◽  
pp. 583-593 ◽  
Author(s):  
Anne K. Berfield ◽  
Douglas Spicer ◽  
Christine K. Abrass
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Smooth Muscle Actin ◽  
Ultrastructural Changes ◽  
Insulin Like Growth Factor ◽  
Glomerular Mesangial Cells ◽  
Muscle Actin ◽  
Igf I

Resident glomerular mesangial cells (MCs) have complex cytoskeletal organizations that maintain functional and structural integrity. The ability of cells to replicate, coordinate movement, change shape, and interact with contiguous cells or extracellular matrix depends on cytoskeletal organization. MCs synthesize insulin-like growth factor (IGF-I), express IGF-I receptors, and respond to IGF-I with increased proliferation. We noted that IGF-I treatment of mesangial cells was associated with a change in morphology. Therefore, these studies were undertaken to define specific IGF-I-mediated changes in cytoskeletal protein organization. Rat MCs were propagated from birth in culture without supplemental insulin. Quiescent, subconfluent cultures were treated with IGF-I (100 nM) for 1 hr. Rearrangements in f-actin, α-smooth muscle actin, β-actin, vimentin, and vinculin were seen by fluorescence microscopy. As the cytoskeleton rearranged, α-smooth muscle actin dissociated from the f-actin bundles and β-actin became polymerized under the leading lamellar edge. Ultrastructural changes were consistent with increased membrane turnover and metabolic activity. The normally sessile mesangial cell was induced by IGF-I to express a wound-healing phenotype characterized by movement and increased pinocytosis. These changes are different from those induced by insulin and have important implications for mesangial cell function.

scholarly journals Constitutive phosphorylation of the receptor for insulinlike growth factor I in cells transformed by the src oncogene.

1990 ◽  
Vol 10 (7) ◽  
pp. 3626-3634 ◽  
Author(s):  
L M Kozma ◽  
M J Weber
Keyword(s):  
Growth Factor ◽  
Beta Subunit ◽  
Transformed Cells ◽  
Receptor Phosphorylation ◽  
Factor I ◽  
Insulinlike Growth Factor ◽  
Igf I ◽  
Growth Factor I ◽  
Insulinlike Growth Factor I ◽  
In Cells

Many oncogene products have been shown to bear strong homology to or to interact with components of normal cellular signal transduction. We have previously shown that a glycoprotein band of 95 kilodaltons (kDa) becomes tyrosine phosphorylated in chick cells transformed by Rous sarcoma virus and that tyrosine phosphorylation of this protein band correlates tightly with phenotypic transformation in cells infected with a large and diverse panel of src mutants (L. M. Kozma, A. B. Reynolds, and M. J. Weber, Mol. Cell. Biol. 10:837-841, 1990). In this communication, we report that a component of the 95-kDa glycoprotein band is related or identical to the 95-kDa beta subunit of the receptor for insulinlike growth factor I (IGF-I). We found that the beta subunit of the IGF-I receptor comigrated on polyacrylamide gels with a component of the 95-kDa glycoprotein region from src-transformed cells under both reducing and nonreducing gel conditions and had a very similar partial phosphopeptide map. To further test the hypothesis that the beta subunit of the IGF-I receptor becomes tyrosine phosphorylated in cells transformed by pp60src, a human cell line that expressed the IGF-I receptor was transformed by src. Comparison of IGF-I receptors immunoprecipitated from normal and transformed cells revealed that the beta subunit of the IGF-I receptor became constitutively tyrosine phosphorylated in src-transformed cells. Moreover, IGF-I receptor phosphorylation induced by src was synergistic with that induced by the hormone: IGF-I-stimulated autophosphorylation of the receptor was much greater in src-transformed cells than in untransformed HOS cells even at maximal concentrations of IGF-I. This increased responsiveness to IGF-I was not due to increases in receptor number, time course of phosphorylation, or affinity for hormone. Finally, no IGF-I-like activity could be detected in culture supernatants collected from the src-transformed cells, suggesting that the increased receptor phosphorylation observed in the src-transformed cells may be mediated by an intracellular mechanism rather than an external autocrine stimulation. Our data demonstrate that the IGF-I receptor becomes constitutively tyrosine phosphorylated in src-transformed cells. This finding raises the possibility that pp60v-src alters growth regulation at least in part by phosphorylating and activating this growth factor receptor.

Studies on Binding and Mitogenic Effect of Insulin and Insulin-Like Growth Factor I in Glomerular Mesangial Cells*

Endocrinology ◽  
1988 ◽  
Vol 122 (6) ◽  
pp. 2788-2795 ◽  
Author(s):  
FRANCESCO G. CONTI ◽  
LILIANE J. STRIKER ◽  
MAXINE A. LESNIAK ◽  
KAREN MACKAY ◽  
JESSE ROTH ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mesangial Cells ◽  
Insulin Like Growth Factor ◽  
Glomerular Mesangial Cells ◽  
Mitogenic Effect ◽  
Factor I ◽  
Growth Factor I

scholarly journals TGFβ acts through PDGFRβ to activate mTORC1 via the Akt/PRAS40 axis and causes glomerular mesangial cell hypertrophy and matrix protein expression

2020 ◽  
Vol 295 (42) ◽  
pp. 14262-14278
Author(s):  
Soumya Maity ◽  
Falguni Das ◽  
Balakuntalam S. Kasinath ◽  
Nandini Ghosh-Choudhury ◽  
Goutam Ghosh Choudhury
Keyword(s):  
Growth Factor ◽  
Matrix Protein ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Kidney Cortex ◽  
Glomerular Mesangial Cells ◽  
Cell Hypertrophy ◽  
Tgfβ Receptor ◽  
Mtorc1 Activation ◽  
Noncanonical Signaling

Interaction of transforming growth factor-β (TGFβ)-induced canonical signaling with the noncanonical kinase cascades regulates glomerular hypertrophy and matrix protein deposition, which are early features of glomerulosclerosis. However, the specific target downstream of the TGFβ receptor involved in the noncanonical signaling is unknown. Here, we show that TGFβ increased the catalytic loop phosphorylation of platelet-derived growth factor receptor β (PDGFRβ), a receptor tyrosine kinase expressed abundantly in glomerular mesangial cells. TGFβ increased phosphorylation of the PI 3-kinase–interacting Tyr-751 residue of PDGFRβ, thus activating Akt. Inhibition of PDGFRβ using a pharmacological inhibitor and siRNAs blocked TGFβ-stimulated phosphorylation of proline-rich Akt substrate of 40 kDa (PRAS40), an intrinsic inhibitory component of mTORC1, and prevented activation of mTORC1 in the absence of any effect on Smad 2/3 phosphorylation. Expression of constitutively active myristoylated Akt reversed the siPDGFRβ-mediated inhibition of mTORC1 activity; however, co-expression of the phospho-deficient mutant of PRAS40 inhibited the effect of myristoylated Akt, suggesting a definitive role of PRAS40 phosphorylation in mTORC1 activation downstream of PDGFRβ in mesangial cells. Additionally, we demonstrate that PDGFRβ-initiated phosphorylation of PRAS40 is required for TGFβ-induced mesangial cell hypertrophy and fibronectin and collagen I (α2) production. Increased activating phosphorylation of PDGFRβ is also associated with enhanced TGFβ expression and mTORC1 activation in the kidney cortex and glomeruli of diabetic mice and rats, respectively. Thus, pursuing TGFβ noncanonical signaling, we identified how TGFβ receptor I achieves mTORC1 activation through PDGFRβ-mediated Akt/PRAS40 phosphorylation to spur mesangial cell hypertrophy and matrix protein accumulation. These findings provide support for targeting PDGFRβ in TGFβ-driven renal fibrosis.

Heparin binding domain of insulin-like growth factor binding protein-5 stimulates mesangial cell migration

1997 ◽  
Vol 273 (6) ◽  
pp. F899-F906 ◽  
Author(s):  
Christine K. Abrass ◽  
Anne K. Berfield ◽  
Dennis L. Andress
Keyword(s):  
Growth Factor ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Binding Protein ◽  
Interactive Effects ◽  
Insulin Like Growth Factor ◽  
Heparin Binding ◽  
Induction Mechanism ◽  
Igf I ◽  
Heparin Binding Domain

Insulin-like growth factor I (IGF-I) binding protein-5 (IGFBP-5) is produced by mesangial cells (MCs) and likely functions to modulate glomerular IGF-I activity. Although IGFBP-5 may be inhibitory for IGF-stimulated MC activity, preliminary studies suggested that IGFBP-5 acts directly on MCs. To investigate this further, we evaluated the effects of IGFBP-5 on rat MC migration. We found that the carboxy-truncated fragment, IGFBP-5-(1–169), inhibited IGF-I-stimulated migration, but intact IGFBP-5 simulated migration when IGF-I was not present. Demonstration that125I-labeled IGFBP-5 directly binds to MCs further supports an independent role for IGFBP-5. Because heparin inhibited MC binding of125I-IGFBP-5, we tested the heparin binding peptide, IGFBP-5-(201–218), for stimulatory activity. IGFBP-5-(201–218) stimulated MC migration, and this effect was inhibited by heparin. Because the disintegrin, kistrin, blocked IGF-I-induced migration but not migration induced by IGFBP-5-(201–218), the migratory induction mechanism for the two peptides is different. These data indicate that separate, specific regions of IGFBP-5 are responsible for interactive effects with IGF-I as well as direct effects on MC activity.

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