Rapamycin inhibits human renal epithelial cell proliferation: Effect on cyclin D3 mRNA expression and stability

Pallet, Nicolas; Thervet, Éric; Corre, Delphine Le; Knebelmann, Bertrand; Nusbaum, Patrick; Tomkiewicz, Céline; Méria, P.; Flinois, Jean‐Pierre; Beaune, Philippe; Legendre, Christophe; Anglicheau, Dany

doi:10.1111/j.1523-1755.2005.00350.x

Cited by 59 publications

(45 citation statements)

References 51 publications

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“…[38][39][40] This pathway has been found to be required for proliferation due to both the general need for increased protein synthesis as well as the specific requirement for activated p70S6K in the expression of cyclin D proteins and entry into cell cycle. [41][42][43] Consistent with the role of Met-induced activation of this pathway in the early proliferative response, gGTCre;Met fl/fl mice exhibited a .70% reduction in activated p70S6K expression 1 day after I/R. Therefore, we believe that the combination of greater initial tubular cell apoptosis and the concomitant reduction in p70S6K activation accounts for the marked reduction in the early proliferative phase of tubule repair seen in mice lacking the Met receptor in the proximal tubule.…”

Section: Discussionsupporting

confidence: 49%

Met Activation Is Required for Early Cytoprotection after Ischemic Kidney Injury

Mason¹,

Hader

Marlier³

et al. 2014

Journal of the American Society of Nephrology

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Renal proximal tubule epithelial cells express high levels of the hepatocyte growth factor receptor Met, and both the receptor and ligand are upregulated after ischemic injury. Activation of the Met receptor after hepatocyte growth factor stimulation in vitro promotes activities involved in kidney repair, including cell survival, migration, and proliferation. However, characterizing the in vivo role of these signaling events in proximal tubule responses to kidney injury has been difficult because global Met knockout results in embryonic lethality due to placental and liver abnormalities. Here, we used gGT-Cre to knockout Met receptor expression selectively in the proximal tubules of mice (gGT-Cre;Met fl/fl ). The kidneys of these mice developed normally, but exhibited increased initial tubular injury, tubular cell apoptosis, and serum creatinine after ischemia/reperfusion compared with gGT-Cre;Met +/+ kidneys. These changes in gGT-Cre;Met fl/fl mice correlated with a selective reduction in PI3K/Akt activation in response to injury and subsequent decreases in inhibitory phosphorylation of the proapoptotic factor Bad and activating phosphorylation of the ribosomal regulatory protein p70-S6 kinase. Moreover, tubular cell proliferation after ischemia/reperfusion was delayed in gGT-Cre;Met fl/fl mice. In conclusion, this study identifies Met-dependent phosphoinositide 3-kinase activation in proximal tubules as a critical determinant of initial tubular cell survival and reparative proliferation after ischemic injury.

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Section: Discussionsupporting

confidence: 49%

Met Activation Is Required for Early Cytoprotection after Ischemic Kidney Injury

Mason¹,

Hader

Marlier³

et al. 2014

Journal of the American Society of Nephrology

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“…Despite of the IL-3 encoding mRNA, destabilizing effects by rapamycin have furthermore been described for other mRNAs including those coding for collagen type 1 [32] and collagen type 3A1 [28] as well as cyclin D 3 mRNA [30]. Similar to IL-3 mRNA, the destabilizing effect of rapamycin on cyclin D 3 mRNA is attributed to two canonical AREs in the 3´-UTR of an mRNA [33].…”

Section: Discussionmentioning

confidence: 95%

Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease–antiprotease system by the mTOR inhibitor rapamycin

Osman

Akool

Doller

et al. 2011

Biochemical Pharmacology

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The mTOR-inhibitor rapamycin is a potent drug used in many immunosuppressive and antiinflammatory therapeutic regimes. In renal transplantation despite its benefical roles rapamycin in some cases can promote renal fibrosis in the kidney but the underlying mechanisms are unknown. In this study, we tested for possible modulatory effects of rapamycin on the cytokine-triggered matrix metalloproteinase 9 (MMP-9)/ tissue inhibitor of metalloproteinase (TIMP)-1 protease-antiprotease system which is critically involved in renal inflammation and fibrosis. Treatment of rat mesangial cells (MC) with rapamycin dosedependently reduced the interleukin 1 (IL-1-triggered increase in gelatinolytic levels as demonstrated by zymography. The reduction in the extracellular MMP-9 content by rapamycin coincided with an attenuation in cytokine-induced steady-state MMP-9 mRNA levels. Conversely, rapamycin caused a dose-dependent increase in cytokine-evoked TIMP-1 expression in a Smad binding element (SBE) -dependent manner. Surprisingly, the attenuation of MMP-9 mRNA levels by rapamycin is accompanied by a potentiation of IL-1-induced MMP-9 promoter activity in which the stimulatory effects by rapamycin are mainly attributed to a proximal AP-1 binding site. Furthermore, the rapamycin-dependent potentiation of MMP-9 expression is accompanied by an amplification of cytokine-triggered activities of nuclear factor B (NF-B) and activator protein 1 (AP-1) transcription factors. Importantly, rapamycin-triggered increase in MMP-9 promoter activity is fully impaired when we used a MMP-9 reporter construct which is under the additional control of the 3´untranslated region (3´-UTR) of MMP-9. Collectively, these data imply that rapamycin inhibits the cytokineinduced MMP-9 mainly through posttranscriptional events and thereby exerts profibrotic activities.

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“…Quantitative real-time PCR estimation of mRNA levels was performed as described previously [28]. Real-time quantitative PCR was performed by using SYBR green I as fluorescent dye (DRR041A,TaKaRa Biotechnology, China).…”

Section: Determination Of Mrna Levels By Quantitative Real-time Pcrmentioning

confidence: 99%

Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

et al. 2006

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The role of the hypoxia-inducible factor (HIF) subunits 1α and 2α in response to hypoxia is well established in lung epithelial cells, whereas little is known about HIF-3α with respect to transcriptional and translational regulation by hypoxia. HIF-3α and HIF-1α are two similar but distinct basic helix-loop-helix-PAS proteins, which have been postulated to activate hypoxia responsive genes in response to hypoxia. Here, we used quantitative real time RT-PCR and immunoblotting to determine the activation of HIF-3α vs. HIF-1α by hypoxia. HIF-3α was strongly induced by hypoxia (1% O 2 ) both at the level of protein and mRNA due to an increase in protein stability and transcriptional activation, whereas HIF-1α protein and mRNA levels enhanced transiently and then decreased because of a reduction in its mRNA stability in A549 cells, as measured on mRNA and protein levels. Interestingly, HIF-3α and HIF-1α exhibited strikingly similar responses to a variety of activating or inhibitory pharmacological agents. These results demonstrate that HIF-3α is expressed abundantly in lung epithelial cells, and that the transcriptional induction of HIF-3α plays an important role in the response to hypoxia in vitro. Our findings suggest that HIF-3α, as a member of the HIF system, is complementary rather than redundant to HIF-1α induction in protection against hypoxic damage in alveolar epithelial cells.

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Rapamycin inhibits human renal epithelial cell proliferation: Effect on cyclin D3 mRNA expression and stability

Abstract: Rapamycin inhibits the proliferative response of HRECs to mitogenic stimuli, and causes cell cycle arrest in the early G(1) phase, not only by a nonspecific process due to inhibition of the p70(S6k) pathway, but also by a direct effect on cyclin D3 mRNA stability.

Cited by 59 publications

References 51 publications

Met Activation Is Required for Early Cytoprotection after Ischemic Kidney Injury

Met Activation Is Required for Early Cytoprotection after Ischemic Kidney Injury

Differential modulation of the cytokine-induced MMP-9/TIMP-1 protease–antiprotease system by the mTOR inhibitor rapamycin

Hypoxia upregulates hypoxia inducible factor (HIF)-3α expression in lung epithelial cells: characterization and comparison with HIF-1α

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