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Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse

Author:
Yin, Guo Nan, Choi, Min Ji, Kim, Woo Jean, Kwon, Mi-Hye, Song, Kang-Moon, Park, Jin-Mi, Das, Nando Dulal, Kwon, Ki-Dong, Batbold, Dulguun, Oh, Goo Taeg, Koh, Gou Young, Kim, Kyu-Won, Ryu, Ji-Kan, Suh, Jun-Kyu
Source:
Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.26 pp. E2731
ISSN:
0027-8424
Subject:
angiogenesis, angiopoietin-1, angiopoietin-2, animal disease models, antibodies, diabetes mellitus, epidermal growth factor, men, mice, nerve tissue, penis, risk factors, small interfering RNA, tyrosine
Abstract:
Penile erection is a neurovascular phenomenon, and erectile dysfunction (ED) is caused mainly by vascular risk factors or diseases, neurologic abnormalities, and hormonal disturbances. Men with diabetic ED often have severe endothelial dysfunction and peripheral nerve damage, which result in poor response to oral phosphodiesterase-5 inhibitors. Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is known to be involved in neuroinflammatory processes and to be related to vascular regression during the embryonic period. Here, we demonstrate in streptozotocin-induced diabetic mice that inhibition of the Ninj1 pathway by administering Ninj1-neutralizing antibody (Ninj1-Ab) or by using Ninj1-knockout mice successfully restored erectile function through enhanced penile angiogenesis and neural regeneration. Angiopoietin-1 (Ang1) expression was down-regulated and angiopoietin-2 expression was up-regulated in the diabetic penis compared with that in controls, and these changes were reversed by treatment with Ninj1-Ab. Ninj1 blockade-mediated penile angiogenesis and neural regeneration as well as recovery of erectile function were abolished by inhibition of Ang1–Tie2 (tyrosine kinase with Ig and epidermal growth factor homology domain-2) signaling with soluble Tie2 antibody or Ang1 siRNA. The present results suggest that inhibition of the Ninj1 pathway will be a novel therapeutic strategy for treating ED.
Agid:
1786416