Long term safety of targeted internalization of cell penetrating peptide crotamine into renal proximal tubular epithelial cells in vivo

Author(s):Show less -

Campeiro, Joana Darc ^[1] ; Dam, Wendy ^[2] ; Monte, Gabriela Guilherme ^[1] ; Portal, Lucas Carvalho ^[1] ; Goncalves de Oliveira, Lilian Caroline ^[3] ; Nering, Marcela Bego ^[1] ; Viana, Gustavo Monteiro ^[4] ; Carapetos, Fernando Cintra ^[5] ; Oliveira, Eduardo Brandt ^[6] ; van den Born, Jacob ^[2] ; Hayashi, Mirian A. F. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo UNIFESP, Dept Farmacol, EPM, Sao Paulo, SP - Brazil

^[2] Univ Groningen, Dept Nephrol, Univ Med Ctr Groningen, Groningen - Netherlands

^[3] Univ Fed Sao Paulo UNIFESP, Dept Biofis, EPM, Sao Paulo, SP - Brazil

^[4] Univ Fed Sao Paulo UNIFESP, Dept Bioquim, EPM, Sao Paulo, SP - Brazil

^[5] Univ Fed Sao Paulo UNIFESP, Dept Patol, EPM, Sao Paulo, SP - Brazil

^[6] Univ Sao Paulo, Dept Bioquim & Imunol, FMRP, Ribeirao Preto - Brazil

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 9, MAR 1 2019.
• Web of Science Citations: 0

Abstract

Activated proximal tubular epithelial cells (PTECs) play a crucial role in progressive tubulo-interstitial fibrosis in native and transplanted kidneys. Targeting PTECs by non-viral delivery vectors might be useful to influence the expression of important genes and/or proteins in order to slow down renal function loss. However, no clinical therapies that specifically target PTECs are available at present. We earlier showed that a cationic cell penetrating peptide isolated from South American rattlesnake venom, named crotamine, recognizes cell surface heparan sulfate proteoglycans and accumulates in cells. In healthy mice, crotamine accumulates mainly in kidneys after intraperitoneal (ip) injection. Herein we demonstrate for the first time, the overall safety of acute or long-term treatment with daily ip administrated crotamine for kidneys functions. Accumulation of ip injected crotamine in the kidney brush border zone of PTECs, and its presence inside these cells were observed. In addition, significant lower in vitro crotamine binding, uptake and reporter gene transport and expression could be observed in syndecan-1 deficient HK-2 PTECs compared to wild-type cells, indicating that the absence of syndecan-1 impairs crotamine uptake into PTECs. Taken together, our present data show the safety of in vivo long-term treatment with crotamine, and its preferential uptake into PTECs, which are especially rich in HSPGs such as syndecan-1. In addition to the demonstrated in vitro gene delivery mediated by crotamine in HK-2 cells, the potential applicability of crotamine as prototypic non-viral (gene) delivery nanocarrier to modulate PTEC gene and/or protein expression was confirmed. (AU)

• FAPESP's process: 13/13392-4 - Evaluation of the use of analogs of crotamine for diagnosis or therapy
• Grantee: Mirian Akemi Furuie Hayashi
• Support Opportunities: Regular Research Grants
• FAPESP's process: 17/02413-1 - Validation of crotamine as a biomarker and evaluation of its potential use in the therapy of human diseases
• Grantee: Mirian Akemi Furuie Hayashi
• Support Opportunities: Regular Research Grants