Cytoskeletal Rearrangement and Signal Transduction in TGF-β1–Stimulated Mesangial Cell Collagen Accumulation

Hubchak, Susan; Runyan, Constance E.; Kreisberg, Jeffrey I.; Schnaper, H. William

doi:10.1097/01.asn.0000076079.02452.92

Cited by 52 publications

(53 citation statements)

References 40 publications

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“…Our observations are supported by a large body of evidence showing direct effects of IGFBP-3 on apoptosis in other epithelial cells (28,29), endothelial cells (30), and, recently, in mesangial cells (31). Stress fiber bundling and the formation of ARC in podocytes have been reported after shear stress (32) and after TGF-␤1 treatment in mesangial cells (33). Our data document that IGFBP-3 has independent effects on apoptosis and actin cytoskeletal rearrangements and that it potentiates the TGF-␤ effects.…”

Section: Discussionsupporting

confidence: 84%

IGF-Binding Protein-3 Modulates TGF-β/BMP-Signaling in Glomerular Podocytes

Peters¹,

Tossidou²,

Achenbach³

et al. 2006

Journal of the American Society of Nephrology

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Podocyte apoptosis initiates progressive glomerulosclerosis in TGF-␤1 transgenic and CD2AP-knockout (CD2AP؊/؊) mice. It was previously shown that in both mouse models, activation of the TGF-␤ pathway is the key event during development of podocyte apoptosis. Furthermore, CD2AP is an important modifier of TGF-␤-induced survival signaling via activation of the phosphoinositol 3-kinase/AKT signaling pathway. This article presents IGF-binding protein-3 (IGFBP-3) as a new modulator of apoptosis and survival signaling in glomerular podocytes. High expression of IGFBP-3 protein in the urine of diseased CD2AP؊/؊ mice was discovered, and IGFBP-3 expression in glomerular podocytes and parietal cells was detected. IGFBP-3 can induce changes in podocyte actin cytoskeleton, leads to apoptosis in cultured murine podocytes, and can enhance TGF-␤1-induced apoptosis in vitro. For studying this process on a molecular level, proapoptotic p38 mitogen-activated protein kinase pathways and antiapoptotic phosphoinositol 3-kinase/AKT pathways were examined in cultured murine podocytes. It was found that IGFBP-3 increments the level of TGF-␤1-induced phosphorylated p38 mitogen-activated protein kinase and decreases the phosphorylation of antiapoptotic AKT. This effect is specific for the co-stimulation of IGFBP-3 with TGF-␤1 because a combination of IGFBP-3 with bone morphogenic protein-7 (BMP-7), another member of the TGF-␤ superfamily, results in apoptosis opposing signaling effects with a strong increase of phosphorylated AKT and subsequent functional effects. These results demonstrate that the IGF/IGFBP axis plays an important role in the development of podocyte apoptosis by modulation of TGF-␤ and BMP-7-induced pro-and antiapoptotic signals.

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Section: Discussionsupporting

confidence: 84%

IGF-Binding Protein-3 Modulates TGF-β/BMP-Signaling in Glomerular Podocytes

Peters¹,

Tossidou²,

Achenbach³

et al. 2006

Journal of the American Society of Nephrology

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“…Interactions with actin influence the behavior and localization of many ion channels (Cantiello, 1995;Furukawa et al, 1996;Levin et al, 1996;Mazzanti et al, 1996;Jing et al, 1997;Nakahira et al, 1998;Shimoni et al, 1999;Shimoni and Rattner, 2001) It is interesting that of the two agents used in this study to disrupt actin filaments, cytochalasin B and latrunculin B, only the latter was capable of inhibiting the increase in calcium current in response to activation of PKC. Differences in the cellular effects of these two agents have been reported previously (Morales et al, 2000;Bricker et al, 2003;Hubchak et al, 2003;Zeidan et al, 2003) and likely reflect the different mode of action of the two agents. Cytochalasins selectively disrupt actin filaments by preventing filament elongation (Morton et al, 2000), whereas latrunculin B sequesters actin monomers (Brozinick et al, 2004), preventing the formation of newly polymerized actin.…”

Section: Discussionmentioning

confidence: 62%

PKC-Induced Intracellular Trafficking of Ca_V2 Precedes Its Rapid Recruitment to the Plasma Membrane

Zhang

Helm²,

Senatore³

et al. 2008

J. Neurosci.

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Activation of protein kinase C (PKC) potentiates secretion in Aplysia peptidergic neurons, in part by inducing new sites for peptide release at growth cone terminals. The mechanisms by which ion channels are trafficked to such sites are, however, not well understood. We now show that PKC activation rapidly recruits new Ca V 2 subunits to the plasma membrane, and that recruitment is blocked by latrunculin B, an inhibitor of actin polymerization. In contrast, inhibition of microtubule polymerization selectively prevents the appearance of Ca V 2 subunits only at the distal edge of the growth cone. In resting neurons, Ca V 2-containing organelles reside in the central region of growth cones, but are absent from distal lamellipodia. After activation of PKC, these organelles are transported on microtubules to the lamellipodium. The ability to traffic to the most distal sites of channel insertion inside the lamellipodium does, therefore, not require intact actin but requires intact microtubules. Only after activation of PKC do Ca V 2 channels associate with actin and undergo insertion into the plasma membrane.

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“…Cells that were grown on 24-well plates with either 6.5 or 20 mM glucose media for 72 h were analyzed for TGF-␤ binding as described previously (35). Briefly, after removal of endogenous TGF-␤ with glycine/NaCl buffer (20 mM glycine, 135 mM NaCl [pH 3.0]), cells were incubated with 125 I-labeled TGF-␤1 (final concentration, 1 to 40 pM in binding buffer; 0.2% BSA, 128 mM NaCl, 5 mM KCl, 5 mM MgSO 4 , 1.2 mM CaCl 2 , 50 mM HEPES [pH 7.4]) for 2 h at 22°C.…”

Section: Tgf-␤ Binding Assaymentioning

confidence: 99%

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

Hayashida¹,

Schnaper²

2004

Journal of the American Society of Nephrology

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Abstract. High ambient glucose activates intracellular signaling pathways to induce cytokines such as TGF-␤1 in the extracellular matrix accumulation of diabetic nephropathy. These same pathways also may directly modulate TGF-␤1 signaling. R-Smad phosphorylation, association with Smad4, and nuclear accumulation after TGF-␤1 treatment (1.0 ng/ml) were significantly higher in mesangial cells that were conditioned to 20 mM glucose for 72 h than mesangial cells in 6.5 mM glucose, suggesting that high glucose enhanced responsiveness to TGF-␤1. Neither TGF-␤1 bioactivity nor TGF-␤ receptor binding was significantly different between in 6.5 and 20 mM glucose-conditioned cultures. Furthermore, adding a neutralizing anti-TGF-␤1 antibody during glucose conditioning did not affect the enhanced Smad responsiveness, indicating that enhancement likely did not result from increased TGF-␤ expression. In contrast, a mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK inhibitor, PD98059, completely abrogated the effect of high glucose. Glucose stimulation of ERK was inhibited by the general protein kinase C (PKC) inhibitor calphostin C and by the PKC␦-specific inhibitor rottlerin, whereas Gö6976, an inhibitor of conventional PKC, had no effect on ERK activity. Specificity of the PKC inhibitors was further verified by PKC␤ and ␦ kinase assay. High glucose increased expression of several PKC isozymes, but only PKC␦ showed proportionally increased membrane translocation and kinase activity in cells that were conditioned to 20 mM glucose. Finally, both ERK and PKC␦ inhibition during glucose conditioning abrogated enhanced ␣1(I) collagen mRNA and promoter induction by TGF-␤1. Taken together, these data strongly suggest that heightened ERK and PKC␦ activity in high ambient glucose conditions interact with the Smad pathway, leading to enhanced responsiveness to TGF-␤1 and increased extracellular matrix production in mesangial cells.

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Cytoskeletal Rearrangement and Signal Transduction in TGF-β1–Stimulated Mesangial Cell Collagen Accumulation

Cited by 52 publications

References 40 publications

IGF-Binding Protein-3 Modulates TGF-β/BMP-Signaling in Glomerular Podocytes

IGF-Binding Protein-3 Modulates TGF-β/BMP-Signaling in Glomerular Podocytes

PKC-Induced Intracellular Trafficking of Ca_V2 Precedes Its Rapid Recruitment to the Plasma Membrane

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

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Cytoskeletal Rearrangement and Signal Transduction in TGF-β1–Stimulated Mesangial Cell Collagen Accumulation

Cited by 52 publications

References 40 publications

IGF-Binding Protein-3 Modulates TGF-β/BMP-Signaling in Glomerular Podocytes

IGF-Binding Protein-3 Modulates TGF-β/BMP-Signaling in Glomerular Podocytes

PKC-Induced Intracellular Trafficking of CaV2 Precedes Its Rapid Recruitment to the Plasma Membrane

High Ambient Glucose Enhances Sensitivity to TGF-β1 via Extracellular Signal—Regulated Kinase and Protein Kinase Cδ Activities in Human Mesangial Cells

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PKC-Induced Intracellular Trafficking of Ca_V2 Precedes Its Rapid Recruitment to the Plasma Membrane