title: A novel proteolysis-resistant cyclic helix B peptide ameliorates kidney ischemia reperfusion injury.
abstract: Helix B surface peptide (HBSP), derived from erythropoietin, displays powerful tissue protection during kidney ischemia reperfusion (IR) injury without erythropoietic side effects. We employed cyclization strategy for the first time, and synthesized thioether-cyclized helix B peptide (CHBP) to improve metabolic stability and renoprotective effect. LC-MS/MS analysis was adopted to examine the stability of CHBP in vitro and in vivo. The renoprotective effect of CHBP in terms of renal function, apoptosis, inflammation, extracellular matrix deposition, and histological injury was also detected in vivo and in vitro. Antibody array and western blot were performed to analyze the signal pathway of involvement by CHBP in the IR model and renal tubular epithelial cells. In this study, thioether-cyclized peptide was significantly stable in vivo and in vitro. One dose of 8nmol/kg CHBP administered intraperitoneally at the onset of reperfusion improved renal protection compared with three doses of 8nmol/kg linear HBSP in a 48h murine IR model. In a one-week model, the one dose CHBP-treated group exhibited remarkably improved renal function over the IR group, and attenuated kidney injury, including reduced inflammation and apoptosis. Interestingly, we found that the phosphorylation of autophagy protein mTORC1 was dramatically reduced upon CHBP treatment. We also demonstrated that CHBP induced autophagy via inhibition of mTORC1 and activation of mTORC2, leading to renoprotective effects on IR. Our results indicate that the novel metabolically stable CHBP is a promising therapeutic medicine for kidney IR injury treatment.
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Yang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhongliang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
authors.forename: Zitong
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Zhao
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Dian
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China; Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: rong.ruiming@zs-hospital.sh.cn.
authors.forename: Ruiming
authors.initials: R
authors.lastname: Rong
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. Electronic address: yqlong@mail.shcnc.ac.cn.
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Key Laboratory of Organ Transplantation, Shanghai, China; Qingpu Branch Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: tyzhu_dr@163.com.
authors.forename: Tongyu
authors.initials: T
authors.lastname: Zhu
keywords: Apoptosis; Autophagy; Cyclic helix B peptide; Inflammation; Kidney ischemia reperfusion injury; Metabolic stability