Editorial Comment
Much progress over the past two decades has improved our understanding of the molecular pathophysiology of erectile dysfunction (ED). However, few medical therapies have been developed since the introduction of phosphodiesterase inhibitors in 1998. Nonetheless, our improved understanding of erectile function and dysfunction has yielded new drug targets over the past several years, including extracellular-related kinase, guanylate cyclase, the RhoA/Rho-kinase pathway, and the endothelin and angiotensin receptors. In 1996, nerve injury-induced protein 1 (Ninjurin 1, Ninj1) was identified as an induced factor after axotomy in neurons and Schwann cells that promote neurite extension [1]. Ninj1 is a cell surface molecule that has roles in regulating nervous and vascular systems. In 2013, Yin et al. examined the role of Ninj1 in the penis and found that Ninj1 levels are upregulated after murine penile cavernous nerve injury, and that Ninj1 inhibition results in increased neurofilament and endothelial cell proliferation [2]. These findings established a foundation for Ninj1 as a novel therapeutic target for cavernous nerve injury-induced ED.
Rather than merely focusing on surgical nerve injury, the same group more recently evaluated the role of Ninj1 in mice with diabetes-induced ED, finding that Ninj1 inhibition facilitates erectile function in this setting as well [3]. In this study, Yin et al. evaluated the efficacy of Ninj1-neutralizing antibody and knockout of Ninj1 in preserving erectile function in streptozotocin (STZ)-treated mice. STZ results in a diabetic condition via pancreatic beta cell toxicity. First, the authors demonstrated increased expression of Ninj1 in the penis of diabetic mice and in mouse cavernous endothelial cells (MCECs) exposed to high glucose conditions mimicking diabetes mellitus. They then evaluated erectile function after intracavernosal injection of Ninj1-blocking antibody in the STZ mice, observing restoration of erectile function to baseline in these mice. However, this positive effect on erectile function was short-lived, indicating that optimization of Ninj1 inhibition is necessary. Ninj1 inhibition also resulted in proliferation of cavernous endothelial cells, and decreased apoptosis in these cells, supporting an angiogenic effect. The authors demonstrated that Ninj1-mediated angiogenic effects arise from signaling via the angiopoietin 1 (Ang1)-tyrosine kinase with Ig and epidermal growth factor homology domain-2 (Tie2) pathway by blocking this pathway. The Ang1–Tie2 pathway is essential in generating functional, nonleaky blood vessels. Ninj1 inhibition was also found to lower levels of reactive oxygen species (ROS), a further positive finding given that high levels of ROS induce apoptosis.
When evaluating the effects of Ninj1 inhibition on nerve content, the authors found not only more neurofilaments in mouse penis undergoing Ninj1 inhibition but higher levels of neuronal nitric oxide synthase (nNOS) in Ninj1-inhibited penis. Preservation of nNOS is significant given that nNOS release from nerve terminals initiates penile erection. These effects on nerve preservation were mediated by secretion of nerve growth factors (NGFs) including brain-derived neurotrophic factor, NGF, and neurotrophin 3, which were markedly upregulated during Ninj1 inhibition.
The authors then expanded their investigations to Ninj1 knockout mice, which had preserved erectile function even in the setting of STZ treatment, further confirming a role for Ninj1 in ED pathogenesis. Finally, while the presence of Ninj1 and Ang1-Tie2 are important in regulation of diabetes-induced ED, the entire pathway has not yet been described. To identify Ninj1 target genes, the authors used gene expression microarray technologies in MCECs exposed to high and normal glucose conditions, and with and without knockdown of Ninj1 using siRNA, finding numerous genes that may play a role in the pathway.
This study is significant in that it describes a novel pathway regulating both angiogenesis as well as neurogenesis in the penis and suggests a novel therapeutic target in the setting of ED. The detailed mechanisms by which Ninj1 is induced, the components of the Ninj1 pathway, and the mechanisms of angiogenesis and neurogenesis mediated by this pathway remain to be defined. In addition, the role of the Ninj1 pathway in humans is currently unknown. It will indeed be interesting to see what future investigations yield in determining whether Ninj1 is a bona fide regulator of human erectile function, and therefore a target for future therapies.
