mtor信號轉導與腎臟損傷

1、mTOR信號轉導與腎臟損傷,,The structure and discovery of rapamycin,Rapamycins are macrocyclic lactones that possess immunosuppressive, antifungal and antitumor properties,Rapa Nui,Structure,The key events for rapamycin,1970 Rapamyc

2、in-producing Streptomyces hygroscopicus taken from Rapa Nui1975 Purification of rapamycin and identification of fungicidal activity 1977 Immunosuppressive activity discovered1984 Antitumour activity discovered 1995 I

3、dentification of the target of rapamycin in mammalian (mTOR)1999 Approved by US FDA for use in preventing host-rejection2003 Approved by FDA for use in drug-eluting stents2007 Approved by FDA for treatment of renal-ce

4、ll carcinoma2008 Approved by FDA for treatment of mantle cell lymphoma2010 Approved by FDA for treatment of tuberous sclerosis2011 Approved by FDA for treatment of pancreatic cancer2013 Crystal structure of mTOR disc

5、overed,,,The structure and composition of mTOR complex,,Annu Rev Immunol. 2012 ; 30: 39–68.,mTOR is a serine/threonine kinase with homology to PI3' kinase,Composition,Structure,,,Upstream mTOR signaling,Annu Rev Immu

6、nol. 2012 ; 30: 39–68.,,,,,Downstream processes of mTOR signaling,Modified from Nature: 493:338-45,The impact of mTOR on disease,Renal cancerPKDKidney transplantationPodocytopathyDNAKI, et al,,Rictor/mTORC2 in tubul

7、ar cell survival and AKIRheb/mTORC1 in fibroblast activation and kidney fibrosisRictor/Mtorc2 in fibroblast activation and kidney fibrosis,Activation of mTORC2 signaling in NRK-52E cells after cisplatin treatment,Knock

8、ing down Rictor inhibits mTORC2 signaling in NRK-52E cells after cisplatin treatment,Down regulating Rictor expression aggravates cisplatin-induced tubular cell apoptosis,Down regulating Rictor expression inhibits tubula

9、r cell autophagy after cisplatin treatment,Metformin inhibits cell apoptosis aggravated by Rictor downregulation in the presence of cisplatin,Creating the mice with tubular cell specific deletion of Rictor,Mice with tubu

10、lar cell specific deletion of Rictor are susceptible to cisplatin-induced AKI,More tubular cell apoptosis is found in tubular-Rictor -/- mice after cisplatin injection,Autophagy is inhibited in tubular cells from the kno

11、ckouts after cisplatin injection,Summary (1),Rictor/mTORC2 protects against cisplatin-induced tubular cell death and AKI.,,Origins and activation of myofibroblast in the kidney,mTORC1mTORC2,?,Rictor/mTORC2 in tubular ce

12、ll survival and AKIRheb/mTORC1 in fibroblast activation and kidney fibrosisRictor/Mtorc2 in fibroblast activation and kidney fibrosis,Activation of Rheb/mTORC1 signaling in interstitial cells from the fibrotic kidneys,

13、Activation of Rheb/mTORC1 signaling in myofibroblasts from the fibrotic kidneys,TGF-β1 promotes Rheb activation and expression in NRK-49F Cells,TGF-β1 promotes mTORC1 signaling activation in NRK-49F Cells,Knocking down R

14、heb inhibits mTORC1 signaling and fibroblast activation induced by TGF-β1,Rapamycin blocks mTORC1 signaling and fibroblast activation induced by TGF-β1,Ectopic expression of Rheb promotes mTORC1 signaling and fibroblast

15、activation,Ectopic Rheb expression induces kidney interstitial fibrosis in mice,Rapamycin ameliorates kidney fibrosis in Rheb transgenics,Speci?c deletion of TSC1 in ?broblasts in mice,Speci?c deletion of TSC1 in ?brobla

16、sts induces focal kidney interstitial fibrosis in mice,Rapamycin ameliorates kidney ?brosis in Fibroblast-Tsc1-/- mice,Summary (2),TSC/Rheb/mTORC1 signaling activation promotes fibroblast activation and kidney interstiti

17、al ?brosis.,Rictor/mTORC2 in tubular cell survival and AKIRheb/mTORC1 in fibroblast activation and kidney fibrosisRictor/mTORC2 in fibroblast activation and kidney fibrosis,Activation of mTORC2 signaling in the fibrob

18、lasts from the fibrotic kidneys,Knocking down Rictor expression blocks TGFβ1-induced NRK-49F cell activation,Creating mice with Specific deletion of Rictor in ?broblast,Specific deletion of Rictor in ?broblast ameliorate

19、s UUO nephropathy in mice,Summary (3),Rictor/mTORC2 regulates ?broblast activation and kidney fibrosis in mice with UUO nephropathy.,Conclusion,Rictor/MtorC2 protects against cisplatin-induced tubular cell apoptos

20、is and AKI; Both TSC/Rheb/mTORC1 and Rictor/mTORC2 signalings play important roles in promoting fibroblast activation and kidney fibrosis.,致謝,科技部973項目（2012CB51761）國家自然科學基金（面上項目, 81070550 ）江蘇省特聘教授計劃啟動經費,