Role of the phosphatidylinositol 3-kinase and mTOR pathways in the regulation of renal fibroblast function and differentiation

Winbanks, Catherine E.; Grimwood, Lauren; Gasser, Anna; Darby, Ian A.; Hewitson, Tim D.; Becker, Gavin J.

doi:10.1016/j.biocel.2006.08.004

Cited by 45 publications

(34 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The reduction in interstitial fibrosis in sirolimus-treated rats with AN was not associated with a decrease in peritubular myofibroblast infiltration. These findings are in agreement with in vitro studies of rat fibroblasts, where everolimus reduced mitogenesis, collagen and TGF-b1 production but promoted myofibroblastic differentiation, as determined by SMA expression [19]. The clinical implications of these contradictory effects of mTOR inhibition on fibroblast turnover are not yet known.…”

Section: Discussionsupporting

confidence: 80%

Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis

Rangan

Coombes

2007

Nephrology Dialysis Transplantation

View full text Add to dashboard Cite

Background. In this study we tested the hypothesis that sirolimus (a target of rapamycin inhibitor that attenuates intrinsic renal and immune cell proliferation) reduces glomerular hypertrophy and tubular epithelial cell (TEC) proliferation, and attenuates the progression of renal scarring and dysfunction, in a non-immune initiated model of focal segmental glomerulosclerosis (FSGS). Methods. Adult male Wistar rats with adriamycin nephropathy (AN) were stratified into two groups, according to proteinuria on day 12, and received either vehicle (dimethylsulphoxide) or sirolimus (0.1 mg/kg) by daily subcutaneous injection, from day 14 until day 49 (n ¼ 8 each). Control animals were also examined (n ¼ 3 each). Results. Sirolimus did not affect the progression of proteinuria, renal dysfunction, hypercholesterolaemia, body weight or alter intraluminal cast formation in AN. Sirolimus prevented the increase in kidney enlargement in AN, and attenuated glomerular capillary tuft expansion, glomerulosclerosis and periglomerular myofibroblast accumulation. In the tubulointerstitium, sirolimus attenuated tubular dilatation, TEC proliferation and interstitial fibrosis. This was accompanied by a reduction in renal cortical TGF-b1, but peritubular myofibroblast accumulation and renal inflammation (glomerular and interstitial ED-1 and CD3-positive cell accumulation), were unaffected. Conclusion. The anti-renotrophic properties of sirolimus were correlated with a reduction in renal scarring in AN. These data suggest that sirolimus has renoprotective effects when administered during the early stages of an FSGS pattern of chronic renal injury.

show abstract

Section: Discussionsupporting

confidence: 80%

Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis

Rangan

Coombes

2007

Nephrology Dialysis Transplantation

View full text Add to dashboard Cite

show abstract

“…Other authors showed the activation of both the MEK/ ERK pathway and the PI3K/Akt pathway in fibroblast proliferation stimulated with ionizing radiation (37) or EGF (31). Moreover, the PI3K-Akt pathway mediates growth and proliferation induced by Wnt3a protein in NIH3T3 (39) and in renal fibroblasts (79). However, this is the first study relating TGF-␤-induced proliferation with PI3K or ERK 1/2 and Ras GTPases.…”

Section: Discussionmentioning

confidence: 67%

“…The participation of PI3K/Akt route in the transduction signaling of several stimuli that promote ECM synthesis and accumulation is also well documented, e.g., in the collagen increase induced by TGF-␤1 in lung fibroblasts (59), by platelet-derived growth factor in cultured fibroblasts (29), and by interleukin-18 in cardiac fibroblasts (57). Winbanks et al (79) reported that the PI3K inhibitor LY294002 induced a 73% reduction in total collagen synthesis in renal fibroblasts. We also reported that TGF-␤1 can upregulate ECM synthesis via PI3K/Akt signaling in fibroblasts (45), and recently, we reported that administration of LY294002 reduced the UUO-induced increase in fibronectin and collagen I expression in vivo (61).…”

Section: Discussionmentioning

confidence: 99%

H-Ras isoform modulates extracellular matrix synthesis, proliferation, and migration in fibroblasts

Fuentes-Calvo

Blázquez‐Medela

Eleno

et al. 2012

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Ras GTPases are ubiquitous plasma membrane transducers of extracellular stimuli. In addition to their role as oncogenes, Ras GTPases are key regulators of cell function. Each of the Ras isoforms exhibits specific modulatory activity on different cellular pathways. This has prompted researchers to determine the pathophysiological roles of each isoform. There is a proven relationship between the signaling pathways of transforming growth factor-β1 (TGF-β1) and Ras GTPases. To assess the individual role of H-Ras oncogene in basal and TGF-β1-mediated extracellular matrix (ECM) synthesis, proliferation, and migration in fibroblasts, we analyzed these processes in embryonic fibroblasts obtained from H-Ras knockout mice ( H-ras−/−). We found that H- ras−/− fibroblasts exhibited a higher basal phosphatidylinositol-3-kinase (PI3K)/Akt activation than wild-type (WT) fibroblasts, whereas MEK/ERK 1/2 activation was similar in both types of cells. Fibronectin and collagen synthesis were higher in H -ras−/− fibroblasts and proliferation was lower in H -ras−/− than in WT fibroblasts. Moreover, H-Ras appeared indispensable to maintain normal fibroblast motility, which was highly restricted in H- ras−/− cells. These results suggest that H-Ras (through downregulation of PI3K/Akt activation) could modulate fibroblast activity by reducing ECM synthesis and upregulating both proliferation and migration. TGF-β1 strongly increased ERK and Akt activation in WT but not in H- ras−/− fibroblasts, suggesting that H-Ras is necessary to increase ERK 1/2 activation and to maintain PI3K downregulation in TGF-β1-stimulated fibroblasts. TGF-β1 stimulated ECM synthesis and proliferation, although ECM synthesis was higher and proliferation lower in H- ras−/− than in WT fibroblasts. Hence, H-Ras activation seems to play a key role in the regulation of these effects.

show abstract

“…The mTOR signaling pathway participates in the activation of macrophages [4,5] and myofibroblasts [6,7,8], indicating the importance of mTOR in the regulation of kidney inflammation and fibrosis. Activation of mTOR most prominently results in the phosphorylation of two downstream targets, the ribosomal S6 Kinase (S6K) and 4E-BP (eukaryotic translation-initiation factor 4E-binding protein), which stimulate ribosome biogenesis and translation to increase cell mass [9,10].…”

Section: Introductionmentioning

confidence: 99%

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Wang

Ding

Zhang

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aim: Aldosterone (Aldo), a mediator of kidney fibrosis, is implicated in the pathogenesis of chronic kidney diseases (CKD). The aim of this study was to evaluate the regulatory role of rapamycin (Rap) in Aldo-induced tubulointerstitial inflammation and fibrosis. Methods: Uninephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and were randomized to receive treatment for 28 days as follows: vehicle infusion (control), 0.75 μg/h Aldo subcutaneous infusion, or Aldo infusion plus 1 mg/kg/day of Rap by intraperitoneal injection. The effect of Rap on Aldo-induced fibrosis and renal inflammation was investigated using Masson's technique, immunohistochemistry, and western blotting. The effects of Rap on the Aldo-induced epithelial-mesenchymal transition (EMT) process and on TNF-α mRNA expression and secretion in cultured HK-2 cells were investigated by immunofluorescent staining, western blot, qRT-PCR and ELISA. Results: An in vivo study indicated that signaling by the mammalian target of Rap (mTOR) was activated in rats in the Aldo group compared to controls, as indicated by up-regulated expression of p-mTOR and p-S6K. In addition, the inflammatory response increased, as evidenced by increases in inflammatory markers (MCP-1, ICAM-1, F4/80), and the accumulation of extracellular matrix (ECM), as indicated by increased collagen I and fibronectin expression and pro-fibrogenic gene (PAI-1 and TGF-β1) expression. These changes were attenuated by Rap treatment. An in vitro study showed that Rap significantly suppressed the Aldo-induced EMT process and TNF-α mRNA expression and secretion in cultured HK-2 cells. Conclusions: Rap can ameliorate tubulointerstitial inflammation and fibrosis by blocking mTOR signaling. Tubular cells may be a major cell type involved in this physiologic process.

show abstract

Role of the phosphatidylinositol 3-kinase and mTOR pathways in the regulation of renal fibroblast function and differentiation

Cited by 45 publications

References 75 publications

Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis

Renoprotective effects of sirolimus in non-immune initiated focal segmental glomerulosclerosis

H-Ras isoform modulates extracellular matrix synthesis, proliferation, and migration in fibroblasts

Rapamycin Attenuates Aldosterone-Induced Tubulointerstitial Inflammation and Fibrosis

Contact Info

Product

Resources

About