Signaling Through PI3K/Akt Mediates Stretch and PDGF-BB-Dependent DNA Synthesis in Bladder Smooth Muscle Cells

Adam, Rosalyn M.; Roth, Jonathan V.; Cheng, Hong-Lin; Rice, Dana C.; Khoury, Joseph El; Bauer, Stuart B.; Peters, Craig A.; Freeman, Michael R.

doi:10.1097/01.ju.0000063980.99368.35

Cited by 61 publications

(66 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Evidence is emerging that mechanical forces may also lead to Akt activation. In vitro, Akt is phosphorylated in endothelial cells by fluid shear stress (23) and by cyclic stretch in pericytes, osteoblasts, and aortic and bladder smooth muscle cells (24,25,27,45). In vivo, myocardial pressure overload and aortic stent implantation stimulate activation of Akt (46,47).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Krepinsky¹,

Li²,

Chang³

et al. 2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Akt activation by mechanical stress has been linked to the generation of the vasodilatory substance nitric oxide in endothelial cells and to proliferation in smooth muscle cells (24,26,27). However, whether strain-induced matrix elaboration involves Akt is unknown.…”

mentioning

confidence: 99%

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Krepinsky¹,

Li²,

Chang³

et al. 2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…12 In addition, stretch-sensitive genes in pBSMC were also found to be PDGF responsive. 13 Published reports have suggested that mechanical stimuli can activate the PDGFR in vascular SMC in vitro.…”

Section: Activation Of the Pdgfr Ex Vivo And In Vitro Induces Tm Exprmentioning

confidence: 99%

“…Following selection and confirmation of Akt knockdown by immunoblot analysis, pBSMC were subjected to PDGF treatment as described previously. 12 In selected experiments, small interfering RNA (siRNA) oligos targeting Fra1 and TM were obtained from Dharmacon (Lafayette, CO) and Santa Cruz Biotechnology, respectively. pBSMC were nucleofected using an Amaxa IIN nucleofector (Amaxa, Gaithersburg, MD) with 1 mol/L nontargeting or gene-specific siRNA oligos, according to the manufacturer's protocol.…”

Section: Rna Interference In Pbsmcmentioning

confidence: 99%

“…We also implicated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and the activator protein-1 (AP-1) transcriptional complex as mediators of DNA synthesis and gene expression, respectively, in primary human bladder SMC (pBSMC) exposed to cyclic stretch relaxation or PDGF. 12,13 Although Akt and AP-1 have been studied independently in many different contexts, the extent to which they interact to regulate smooth muscle remodeling remains unknown. In this study, we show that the PDGFR is activated in the bladder wall in response to distension and describe a novel Akt-and AP-1-dependent pathway in pBSMC that regulates expression of thrombomodulin (TM).…”

mentioning

confidence: 99%

See 1 more Smart Citation

An Akt- and Fra-1-Dependent Pathway Mediates Platelet-Derived Growth Factor-Induced Expression of Thrombomodulin, a Novel Regulator of Smooth Muscle Cell Migration

Ramachandran

Ranpura

Gong

et al. 2010

The American Journal of Pathology

Self Cite

View full text Add to dashboard Cite

Overdistension of hollow organs evokes pathological changes characterized by smooth muscle remodeling. Mechanical stimuli induce smooth muscle cell (SMC) growth through acute activation of signaling cascades and by increased expression of soluble mitogens. Physical forces have also been implicated in ligandindependent activation of receptor tyrosine kinases, including the platelet-derived growth factor (PDGF) receptor, although the extent to which this occurs in intact tissue is unknown. Previously, we implicated Akt and activator protein-1 (AP-1) as mediators of growth and gene expression in SMC exposed to cyclic stretch or PDGF. Here we show that bladder wall distension leads to PDGFR activation and identify thrombomodulin (TM) as an Akt and AP-1 target in SMC. We demonstrate that TM, also induced by bladder stretch injury, is regulated at the transcriptional level by the AP-1 components c-jun and Fra1. Mutation of an AP-1 motif at ؊2010/؊2004 abolished both AP-1 binding and PDGF responsiveness of the TM promoter. Fra1 silencing diminished PDGF-induced TM expression and SMC cell cycle transit. In contrast, TM knockdown did not affect cell growth but attenuated PDGF-stimulated SMC migration. Taken together, these results reveal new facets of TM regulation in SMC and provide the first demonstration of a role for endogenous TM in PDGF-induced cell migration. Moreover, TM induction on bladder injury suggests that it may be a biomarker for pathological smooth muscle remodeling.

show abstract

Stable hydrogel adhesion to polydimethylsiloxane enables cyclic mechanical stimulation of 3D‐bioprinted smooth muscle constructs

Xuan

Гуревич

Christiansen

et al. 2023

Biotech & Bioengineering

View full text Add to dashboard Cite

During normal urination, smooth muscle cells (SMCs) in the lower urinary tract (LUT) are exposed to mechanical signals that have a critical impact on tissue structure and function. Nevertheless, the mechanisms underlying the maintenance of the contractile phenotype of SMCs remain poorly understood. This is due, in part, to a lack of studies that have examined the effects of mechanical loading using three‐dimensional (3D) models. In this study, surface modifications of polydimethylsiloxane (PDMS) membrane were evaluated to investigate the effects of cyclic mechanical stimulation on SMC maturation in 3D constructs. Commercially available cell stretching plates were modified with amino or methacrylate groups to promote adhesion of 3D constructs fabricated by bioprinting. After 6 days of stimulation, the effects of mechanical stimulation on the expression of contractile markers at the mRNA and protein levels were analyzed. Methacrylate‐modified surfaces supported stable adhesion of the 3D constructs to the membrane and facilitated cyclic mechanical stimulation, which significantly increased the expression of contractile markers at the mRNA and protein levels. These effects were found to be mediated by activation of the p38 MAPK pathway, as inhibition of this pathway abolished the effects of stimulation in a dose‐dependent manner. These results provide valuable insights into the role of mechanical signaling in maintaining the contractile phenotype of bladder SMCs, which has important implications for the development of future treatments for LUT diseases.

show abstract

Signaling Through PI3K/Akt Mediates Stretch and PDGF-BB-Dependent DNA Synthesis in Bladder Smooth Muscle Cells

Cited by 61 publications

References 20 publications

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells

An Akt- and Fra-1-Dependent Pathway Mediates Platelet-Derived Growth Factor-Induced Expression of Thrombomodulin, a Novel Regulator of Smooth Muscle Cell Migration

Stable hydrogel adhesion to polydimethylsiloxane enables cyclic mechanical stimulation of 3D‐bioprinted smooth muscle constructs

Contact Info

Product

Resources

About