Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1842, Issue 11, Pages 2306-2317Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2014.09.001
Keywords
Cyclic helix B peptide; Metabolic stability; Kidney ischemia reperfusion injury; Autophagy; Apoptosis; Inflammation
Funding
- National Natural Science Foundation of China [81270832, 81270833, 81021062, 81370852, 81123004, 81400752, 21302201]
- Science and Technology Commission of Shanghai Municipality [12ZR1405500, 13ZR1447700]
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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 8 nmol/kg CHBP administered intraperitoneally at the onset of reperfusion improved renal protection compared with three doses of 8 nmol/kg linear HBSP in a 48 h 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. (C) 2014 Elsevier B.V. All rights reserved.
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