The l-isoform but not d-isoforms of a JNK inhibitory peptide protects pancreatic beta-cells.
The activation of c-jun N-terminal kinase (JNK) in pancreatic islets is associated with impaired function and viability, and JNK inhibitory peptides (JNKIs) are cytoprotective. In particular, l-isoforms of JNKIs were shown to improve islets viability, while the d-retroinverso isoform of JNKI (RI-JNKI), with a higher therapeutic potential due to longer half-life, has not been studied. We compared the cytoprotective properties of L-JNKI and RI-JNKI. Treatment of murine islets with L-JNKI resulted in preservation of islet equivalents and greater percentage of viable beta-cells in culture. In contrast, RI-JNKI was not protective. We found that L-JNKI but not RI-JNKI prevents endogenous c-jun phosphorylation in insulinoma cells. Moreover, RI-JNKI induced islet cells necrosis and activates the p-38 kinase. In conclusion, L-JNKI directly affects beta-cells and ameliorates islet viability and function, while RI-JNKI has toxic effects, limiting its biological application to islet cell biology.
Fornoni
Alessia
A
Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue, Miami, FL 33136, USA. afornoni@med.miami.edu
Cobianchi
Lorenzo
L
Sanabria
Nahir Y
NY
Pileggi
Antonello
A
Molano
R Damaris
RD
Ichii
Hirohito
H
Rosero
Samuel
S
Inverardi
Luca
L
Ricordi
Camillo
C
Pastori
Ricardo L
RL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects*; D007527:Isoenzymes; D007536:Isomerism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D020033:Protein Isoforms; D013552:Swine
D007527:Isoenzymes; D020033:Protein Isoforms; D048031:JNK Mitogen-Activated Protein Kinases