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

Guo Nan Yin, Min Ji Choi, Woo Jean Kim, Mi Hye Kwon, Kang Moon Song, Jin Mi Park, Nando Dulal Das, Ki Dong Kwon, Dulguun Batbold, Goo Taeg Oh, Gou Young Koh, Kyu Won Kim, Ji Kan Ryu, Jun Kyu Suh

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

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.

Original languageEnglish
Pages (from-to)E2731-E2740
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number26
DOIs
StatePublished - 1 Jul 2014

Keywords

  • Diabetes mellitus
  • Male sexual dysfunction
  • Peripheral neuropathy

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