Cell permeable peptide of JNK inhibitor prevents islet apoptosis immediately after isolation and improves islet graft function.
Although application of the Edmonton protocol has markedly improved outcomes for pancreatic islet transplantation, the insulin independence rate after islet transplantation from one donor pancreas has proven to remain low. During the isolation process and subsequent clinical transplantation, islets are subjected to severe adverse conditions that impair survival and ultimately contribute to graft failure. Pancreas preservation with the two-layer method (TLM) has proven to improve transplant results by protecting isolated islets against apoptosis through the mitochondrial pathway. However, pancreas storage with TLM cannot protect against activation of c-Jun NH2-terminal kinase (JNK) in isolated islets. This study investigated whether delivery of a JNK inhibitory peptide (JNKI) via the protein transduction system can prevent apoptosis of islet cells immediately after isolation. For efficient delivery of the (JNKI into isolated islets, we synthesized JNKI as a C-terminal fusion peptide with the 11-arginine protein transduction domain (11R-JNKI). 11R efficiently delivered the JNKI into isolated islets and 11R-JNKI prevented islet apoptosis immediately after isolation and improved islet graft function. These findings suggest that peptide drugs could be useful for the prevention of the impairment of islet cells and lead to improvement in the outcomes for pancreatic islet transplantation.
Noguchi
Hirofumi
H
Department of Transplantation and Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan. noguchih@kuhp.kyoto-u.ac.jp
Nakai
Yusuke
Y
Matsumoto
Shinichi
S
Kawaguchi
Miho
M
Ueda
Michiko
M
Okitsu
Teru
T
Iwanaga
Yasuhiro
Y
Yonekawa
Yukihide
Y
Nagata
Hideo
H
Minami
Kohtaro
K
Masui
Yumi
Y
Futaki
Shiroh
S
Tanaka
Koichi
K
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002463:Cell Membrane Permeability; D003080:Cold Temperature; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology*; D007515:Islets of Langerhans / Q000502:physiology*; D016381:Islets of Langerhans Transplantation / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009926:Organ Preservation; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*; D013552:Swine; D014161:Transduction, Genetic
D010446:Peptide Fragments; D048031:JNK Mitogen-Activated Protein Kinases