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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

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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 3

Hexagonal morphology of umbrella cells is preserved in p75KO mice and with LM11A-31 administration after SCI.

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Hexagonal morphology of umbrella cells is preserved in p75KO mice and wi...
(A) Without injury, the luminal surface of the bladder exhibited the well-characterized polyhedral morphology with ridges that demarcate cell boundaries (blue lines and arrows; ref. 15). At 7 hours after injury, however, the surface morphology was drastically altered, with loss of the characteristic junctional ridges. By 2 days postinjury (dpi), umbrella cells were regenerated, but they were smaller in size than those without injury, although they established polyhedral morphology (red arrows). (B) With intravesical instillation of LM11A-31 immediately after SCI, however, umbrella cell loss was completely blocked, with intact polyhedral ridges at both 7 hours and 2 days after injury (blue lines and arrows). (C) At 7 hours after injury, the luminal surface of the bladder from p75KO mice was visually indistinguishable from that of the control bladder. Blue dotted lines mark the hexagonal boundaries of umbrella cells. Higher-magnification images illustrate the cell boundaries between neighboring cells (arrows). (D) H&E staining of the control and LM11A-31–treated bladders. Note the preservation of the urothelium at 1 day after injury with LM11A-31, while very few urothelial cells are visible in vehicle-treated bladder. LM11A-31 also prevented chronic urothelial hyperplasia and detrusor hypertrophy of the bladder at 10 days after injury. The bladder morphology appears similar to that of the uninjured control bladder. Urothelial and muscle layers of the bladder wall are indicated by U and M, respectively, and the bladder lumen is indicated by L. Scale bar: 250 μm. Experiments were performed 3 times, and representative ones are shown.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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