title: Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse.
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.
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Guo Nan
authors: GN
authors: Yin
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Min Ji
authors: MJ
authors: Choi
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Woo Jean
authors: WJ
authors: Kim
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Mi-Hye
authors: MH
authors: Kwon
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Kang-Moon
authors: KM
authors: Song
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Jin-Mi
authors: JM
authors: Park
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Nando Dulal
authors: ND
authors: Das
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Ki-Dong
authors: KD
authors: Kwon
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea;
authors: Dulguun
authors: D
authors: Batbold
authors: Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea;
authors: Goo Taeg
authors: GT
authors: Oh
authors: National Research Laboratory of Vascular Biology and Stem Cells andGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea; and.
authors: Gou Young
authors: GY
authors: Koh
authors: Neurovascular Coordination Research Center, College of Pharmacy andResearch Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea.
authors: Kyu-Won
authors: KW
authors: Kim
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea; jksuh@inha.ac.kr rjk0929@inha.ac.kr.
authors: Ji-Kan
authors: JK
authors: Ryu
authors: National Research Center for Sexual Medicine andDepartment of Urology, Inha University School of Medicine, Incheon 400-711, Korea; jksuh@inha.ac.kr rjk0929@inha.ac.kr.
authors: Jun-Kyu
authors: JK
authors: Suh
mesh_terms: D000704:Analysis of Variance; D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D017931:DNA Primers / Q000235:genetics; D048909:Diabetes Complications / Q000188:drug therapy*; D007172:Erectile Dysfunction / Q000188:drug therapy*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology*; D042787:Receptor, TIE-2 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D042683:Angiopoietin-1; C467628:Angpt1 protein, mouse; D057134:Antibodies, Neutralizing; D015816:Cell Adhesion Molecules, Neuronal; D017931:DNA Primers; D009414:Nerve Growth Factors; C484439:Ninj1 protein, mouse; D042787:Receptor, TIE-2; C079086:Tek protein, mouse
keywords: diabetes mellitus; male sexual dysfunction; peripheral neuropathy