Effect of Rapamycin on Hepatocyte Function and Proliferation Induced by Growth Factors

Tomiya, Tomoaki; Yamaoka, Makoto; Inoue, Yukiko; Nishikawa, Tatsuya; Yanase, Mikio; Ikeda, Hitoshi; Tejima, Kazuaki; Nagashima, Kōzō; Watanabe, Naoko; Omata, Masao; Fujiwara, Kenji

doi:10.1159/000098420

Cited by 5 publications

(8 citation statements)

References 75 publications

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“…Our observations are corroborated by experimental studies, indicating that the mTOR pathway is indeed relevant for modulating HGF expression. 46–47 Rapamycin (as inhibitor) and Leucin (as stimulator) exert their influence on HGF expression and secretion through the mTOR pathway. 46–47 Furthermore, we revealed a statistically significant overrepresentation of HGF-related genes in the amyotrophic lateral sclerosis signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…46–47 Rapamycin (as inhibitor) and Leucin (as stimulator) exert their influence on HGF expression and secretion through the mTOR pathway. 46–47 Furthermore, we revealed a statistically significant overrepresentation of HGF-related genes in the amyotrophic lateral sclerosis signaling pathway. In this context, experimental data support that HGF might improve survival of motor neurons and the clinical course of amyotrophic lateral sclerosis.…”

Section: Discussionmentioning

confidence: 99%

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Genome-Wide Association Study for Endothelial Growth Factors

Lieb

Chen

Larson

et al. 2015

Circ Cardiovasc Genet

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Background Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2) and hepatocyte growth factor (HGF) play important roles in angiogenesis, vascular remodeling, local tumor growth and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown. Methods and Results We performed a genome-wide association study for circulating Ang-2, sTie-2, and HGF in 3571 Framingham Heart Study (FHS) participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania (SHIP). In multivariable-adjusted models, sTie-2 and HGF concentrations were associated with single nucleotide polymorphisms (SNPs) in the genes encoding the respective biomarkers (top p=2.40×10−65 [rs2273720] and 3.64×10−19 [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (p=5.05×10−8 in FHS and 8.39×10−5 in SHIP). Furthermore, SNPs in the AB0 gene were associated with sTie-2 (top SNP rs8176693 with p=1.84×10−33 in FHS; p=2.53×10−30 in SHIP) and Ang-2 (rs8176746 with p=2.07×10−8 in FHS; p=0.001 in SHIP) levels on a genome-wide significant level. The top genetic loci explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the inter-individual variation in biomarker levels. Conclusions Genetic variation contributes to the inter-individual variation in growth factor levels and explains a modest proportion of circulating HGF, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study for Endothelial Growth Factors

Lieb

Chen

Larson

et al. 2015

Circ Cardiovasc Genet

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“…To assess this issue, substances such as geldanamycin [25], radicicol [26], quercetin [27], KNK 437 [28], cyclosporin A [29], rapamycin [30] or FK 506 [31] were tested which interfere in the signaling between MR and hsp 90, hsp 70 and immunophilins.…”

Section: Discussionmentioning

confidence: 99%

“…To interrupt the tubulogenic signal of aldosterone on the level of hsp 90, hsp 70 and immunophilins, the following substances were applied: geldanamycin (3,6 x 10 -6 M, Biomol, Hamburg, Germany) [25], radicicol (1 x 10 -6 M, Sigma, Taufkirchen, Germany) [26], quercetin (2 x 10 -4 M, Biozol, Eching, Germany) [27], KNK 437 (1 x 10 -4 M, Calbiochem, Darmstadt, Germany) [28], cyclosporin A (2 x 10 -6 M, Fluka, Taufkirchen, Germany) [29], rapamycin (2,2 x 10 -9 M, Assay designs, Michigan, USA) [30] and FK 506 (2 x 10 -8 M, Sigma) [31]. Concentration range of substances were applied as seen in literature.…”

Section: Perfusion Culture To Generate Renal Tubulesmentioning

confidence: 99%

Mineralocorticoid Receptor, Heat Shock Proteins and Immunophilins Participate in the Transmission of the Tubulogenic Signal of Aldosterone

Minuth¹,

Blattmann²,

Denk³

et al. 2008

JEBP

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Aldosterone exhibits a tubulogenic activity on renal stem/progenitor cells. Little information is available about the signaling between the mineralocorticoid receptor (MR) and the proteins in the cytoplasm. To obtain information, renal stem/progenitor cells from neonatal rabbit were cultured at the interface of an artificial polyester interstitium in a perfusion container for 13 days. Development was registered with Soybean Agglutinin (SBA). Microscopy revealed that treatment with aldosterone (1 x 10 -7 M) resulted in numerous SBA-labeled tubules. Interference with mineralocorticoid receptor (MR) and heat shock protein (hsp) 90 using geldanamycin (3,6 x 10 -6 M) or radicicol (1 x 10 -6 M) showed a lack of tubule development. Disturbing MR and hsp 70 with quercetin (2 x 10 -4 M) and KNK 437 (1 x 10 -4 M) generated SBAlabeled cell cluster but not structured tubules. Interference with MR and immunophilins by cyclosporin A (2 x 10 -6 M) and rapamycin (2,2 x 10 -9 M) did not influence the generation of numerous SBA-labeled tubules. In contrast, administration of FK 506 (2 x 10 -8 M) resulted in a lack of tubule development. Thus, the signal for development of tubules induced by aldosterone is mediated by interaction of MR, hsp 90, hsp 70 and immunophilin FKBP 12.

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“…Common signaling pathways such as ERK1/2 (extracellular signal‐regulated kinase 1/2) and mTOR (mammalian target of rapamycin) are reported to be activated by several types of growth factors 1 . In addition, metabolic or nutritional stimuli, especially those induced by amino acids through an mTOR‐dependent signaling pathway, are considered to be significant in hepatocyte proliferation 4–6 . The innate immune system also contributes to the initiation of liver regeneration 7–9 .…”

Section: Introductionmentioning

confidence: 99%

Impaired liver regeneration in acute liver failure: the significance of cross‐communication of growth associated factors in liver regeneration

Tomiya

Omata²,

Imamura

et al. 2008

Hepatology Research

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Liver regeneration is considered to be retarded or suppressed in patients with acute liver failure. However, the mechanisms for this suppression remain to be elucidated. In order to evaluate deficiencies in liver regeneration in patients with acute liver failure, we focused on the cross-communication of growth-associated factors in experimental models. In primary cultured rat hepatocytes, the levels of cellular p53 and transforming growth factor-alpha (TGF-alpha), as well as DNA synthesis increased by the addition of hepatocyte growth factor (HGF). When p53 activity was suppressed, TGF-alpha expression and DNA synthesis were reduced. DNA synthesis was also reduced when TGF-alpha activity was suppressed. In rats after partial hepatectomy, hepatic HGF and p53 protein levels increased, followed by an increase of hepatic TGF-alpha levels and hepatocyte proliferation. Circulating levels of HGF and TGF-alpha correlated with changes in the hepatic levels. The suppression of TGF-alpha activity reduced the proliferation of hepatocytes in these rats. In patients suffering from acute hepatitis, serum HGF levels increased followed by an increase of serum TGF-alpha levels. In contrast, in patients with acute liver failure, the increase of serum TGF-alpha levels was suppressed depending on the severity of hepatic failure, even though serum HGF levels markedly increased. The patients' hepatic levels were consistent with serum levels. Cross-communication of growth associated factors may be important in the progression of liver regeneration, and impaired regenerative capacity in patients with acute liver failure may be attributable, at least in part, to a disruption of communication of growth-associated factors.

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Effect of Rapamycin on Hepatocyte Function and Proliferation Induced by Growth Factors

Cited by 5 publications

References 75 publications

Genome-Wide Association Study for Endothelial Growth Factors

Genome-Wide Association Study for Endothelial Growth Factors

Mineralocorticoid Receptor, Heat Shock Proteins and Immunophilins Participate in the Transmission of the Tubulogenic Signal of Aldosterone

Impaired liver regeneration in acute liver failure: the significance of cross‐communication of growth associated factors in liver regeneration

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