title: Cyclic helix B peptide inhibits ischemia reperfusion-induced renal fibrosis via the PI3K/Akt/FoxO3a pathway.
abstract: Renal fibrosis is a main cause of end-stage renal disease. Clinically, there is no beneficial treatment that can effectively reverse the progressive loss of renal function. We recently synthesized a novel proteolysis-resistant cyclic helix B peptide (CHBP) that exhibits promising renoprotective effects. In this study, we evaluated the effect of CHBP on renal fibrosis in an in vivo ischemia reperfusion injury (IRI) model and in vitro TGF-β-stimulated tubular epithelial cells (TCMK-1 and HK-2) model. In the IRI in vivo model, mice were randomly divided into sham (sham operation), IR and IR + CHBP groups (n = 6). CHBP (8 nmol/kg) was administered intraperitoneally at the onset of reperfusion, and renal fibrosis was evaluated at 12 weeks post-reperfusion. Our results showed that CHBP markedly attenuated the IRI-induced deposition of collagen I and vimentin. In the in vitro model, CHBP reversed the TGF-β-induced down-regulation of E-cadherin and up-regulation of α-SMA and vimentin. Furthermore, CHBP inhibited the phosphorylation of Akt and Forkhead box O 3a (FoxO3a), whose anti-fibrotic effect could be reversed by the 3-phosphoinositide-dependent kinase-1 (PI3K) inhibitor wortmannin as well as FoxO3a siRNA. These findings demonstrate that CHBP attenuates renal fibrosis and the epithelial-mesenchymal transition of tubular cells, possibly through suppression of the PI3K/Akt pathway and thereby the inhibition FoxO3a activity.
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. esuperyc@163.com.|Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China. esuperyc@163.com.|Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. esuperyc@163.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Chinese Traditional Medicine, Shanghai University of Chinese Traditional Medicine, Shanghai, 201203, China. hudiezhilan@163.com.|The Faculty of Life Science and Computing, London Metropolitan University, London, N7 8DB, UK. hudiezhilan@163.com.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China. yzhang_med@fudan.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. ljlmjw@163.com.|Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China. ljlmjw@163.com.
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. xu.ming@zs-hospital.sh.cn.|Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China. xu.ming@zs-hospital.sh.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. yqlong@mail.shcnc.ac.cn.
authors.forename: Yaqiu
authors.initials: Y
authors.lastname: Long
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. rong.ruiming@zs-hospital.sh.cn.|Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China. rong.ruiming@zs-hospital.sh.cn.|Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. rong.ruiming@zs-hospital.sh.cn.
authors.forename: Ruiming
authors.initials: R
authors.lastname: Rong
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. tyzhu_dr@163.com.|Shanghai Key Laboratory of Organ Transplantation, 180 Fenglin Road, Shanghai, 200032, China. tyzhu_dr@163.com.|Qingpu Branch Zhongshan Hospital, Fudan University, 1158 Gongyuan Road East, Shanghai, 201700, China. tyzhu_dr@163.com.
authors.forename: Tongyu
authors.initials: T
authors.lastname: Zhu
mesh_terms: D000818:Animals; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005355:Fibrosis; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000098:blood supply*; D007674:Kidney Diseases / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010456:Peptides, Cyclic / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015427:Reperfusion Injury / Q000150:complications*; D016212:Transforming Growth Factor beta / Q000502:physiology
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D010456:Peptides, Cyclic; D016212:Transforming Growth Factor beta; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt