Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury
Jae Cheon Ryu, … , Margaret A. Vizzard, Sung Ok Yoon
Jae Cheon Ryu, … , Margaret A. Vizzard, Sung Ok Yoon
Published March 26, 2018
Citation Information: J Clin Invest. 2018;128(5):1772-1786. https://doi.org/10.1172/JCI97837.
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Research Article Neuroscience

Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury

Abstract

Loss of bladder control is a challenging outcome facing patients with spinal cord injury (SCI). We report that systemic blocking of pro–nerve growth factor (proNGF) signaling through p75 with a CNS-penetrating small-molecule p75 inhibitor resulted in significant improvement in bladder function after SCI in rodents. The usual hyperreflexia was attenuated with normal bladder pressure, and automatic micturition was acquired weeks earlier than in the controls. The improvement was associated with increased excitatory input to the spinal cord, in particular onto the tyrosine hydroxylase–positive fibers in the dorsal commissure. The drug also had an effect on the bladder itself, as the urothelial hyperplasia and detrusor hypertrophy that accompany SCI were largely prevented. Urothelial cell loss that precedes hyperplasia was dependent on p75 in response to urinary proNGF that is detected after SCI in rodents and humans. Surprisingly, death of urothelial cells and the ensuing hyperplastic response were beneficial to functional recovery. Deleting p75 from the urothelium prevented urothelial death, but resulted in reduction in overall voiding efficiency after SCI. These results unveil a dual role of proNGF/p75 signaling in bladder function under pathological conditions with a CNS effect overriding the peripheral one.

Authors

Jae Cheon Ryu, Katharine Tooke, Susan E. Malley, Anastasia Soulas, Tirzah Weiss, Nisha Ganesh, Nabila Saidi, Stephanie Daugherty, Uri Saragovi, Youko Ikeda, Irina Zabbarova, Anthony J. Kanai, Mitsuharu Yoshiyama, H. Francis Farhadi, William C. de Groat, Margaret A. Vizzard, Sung Ok Yoon

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Figure 1

ProNGF is released into the urine in rodents and humans within hours of SCI.

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ProNGF is released into the urine in rodents and humans within hours of ...
(A) ProNGF is released into the urine almost immediately after spinal cord transection in mice. The blots were probed with anti-proNGF and pan-NGF antibodies. There was little mature NGF detectable in the urine at these time points. (B) Quantification of proNGF by Western blotting. Within-subject comparison was significant at P = 0.003 based on repeated measures of 1-way ANOVA after Greenhouse-Geisser correction, which resulted in P < 0.01. Subsequent pairwise comparisons were made using Bonferroni correction. (C) Quantification of proNGF detected in mouse urine by proNGF-specific ELISA. Note that mature NGF was not detected by mature NGF-specific ELISA. (D) Immunoprecipitation/Western analyses of urine samples illustrate that the bands detected with proNGF antibody in A are indeed proNGF. Mouse urine samples were immunoprecipitated with 27/21 mature NGF antibody and probed with proNGF antibody. (E) ProNGF is detected in the urine after contusion injuries in mice. (F) ProNGF is present in the urine after spinal cord transection in rats. Mature NGF was not detected by mature NGF-specific ELISA. (G) ProNGF was also detected in human urine after SCI. The upper blot was probed with proNGF-specific antibody (*artifact), while the lower blot was probed with pan-NGF antibody (H-20). Note that recombinant proNGF and mature NGF were included as controls. Based on human proNGF-specific ELISA, the amount of proNGF was 1 and 46 pg/mg for 3 and 6 hours after injury, respectively. Note that 3- and 6-hour urine samples were collected from 2 different individuals. ELISA assays also failed to detect mature NGF as in Western blotting. C, urine from healthy control without SCI.