Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Aug;40(6):1460-1469.
doi: 10.1002/nau.24704. Epub 2021 May 20.

Antifibrosis treatment by inhibition of VEGF, FGF, and PDGF receptors improves bladder wall remodeling and detrusor overactivity in association with modulation of C-fiber afferent activity in mice with spinal cord injury

Joonbeom Kwon  1   2   3 , Eun-Ju Lee  2 , Hyun-Jung Cho  2 , Ji-Ae Jang  2 , Min-Su Han  2 , Eunkyoung Kwak  4 , Haesoo Kim  5 , Jihyun An  5 , Donghwi Park  6 , Seungwoo Han  7 , Nobutaka Shimizu  3 , Takahisa Suzuki  3 , Ei-Ichiro Takaoka  3 , Naoki Yoshimura  3
Affiliations

Antifibrosis treatment by inhibition of VEGF, FGF, and PDGF receptors improves bladder wall remodeling and detrusor overactivity in association with modulation of C-fiber afferent activity in mice with spinal cord injury

Joonbeom Kwon et al. Neurourol Urodyn. 2021 Aug.

Abstract

Aims: Spinal cord injury (SCI) above the sacral level causes bladder dysfunction and remodeling with fibrosis. This study examined the antifibrotic effects using nintedanib, an inhibitor of vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors, on detrusor overactivity (DO) and bladder fibrosis, as well as the modulation mechanisms of C-fiber afferent pathways.

Methods: Thirty female C57BL/6 mice were divided into group A (spinal intact), group B (SCI with vehicle), and group C (SCI with nintedanib). At 2 weeks after SCI, vehicle or 50 mg/kg nintedanib was administered subcutaneously for 2 weeks. Then, cystometry was conducted, followed by RT-PCR measurements of fibrosis-related molecules, muscarinic, β-adrenergic, TRP and purinergic receptors in the bladder or L6-S1 dorsal root ganglia (DRG). Trichrome stain and Western blot analysis of transforming growth factor-beta and fibronectin were performed in the bladder. TRPV1 expression in L6 DRG was measured by immunohistochemistry.

Results: In cystometry, intercontraction intervals, nonvoiding contractions, voided volume, and voiding efficiency were significantly improved in group C versus group B. RT-PCR, Western blotting, and trichrome staining revealed the fibrotic changes in the bladder of group B, which was improved in group C. Increased messenger RNA levels of TRPV1, TRPA1, P2X2 , and P2X3 in DRG of group B were significantly decreased in group C. TRPV1 immunoreactivity in DRG was increased in group B, but decreased in group C.

Conclusions: Nintedanib improves storage and voiding dysfunctions and bladder fibrosis in SCI mice. Also, nintedanib-induced improvement of DO is associated with reduced expression of C-fiber afferent markers, suggesting the modulation of bladder C-fiber afferent activity.

Keywords: bladder fibrosis; detrusor overactivity; spinal cord injury.

PubMed Disclaimer

Comment in

References

REFERENCES

    1. Azadzoi KM , Tarcan T , Kozlowski R , Krane RJ , Siroky MB . Overactivity and structural changes in the chronically ischemic bladder. J Urol. 1999;162:1768-1778.
    1. Iguchi N , Dönmez MI , Malykhina AP , Carrasco A Jr , Wilcox DT . Preventive effects of a HIF inhibitor, 17-DMAG, on partial bladder outlet obstruction-induced bladder dysfunction. Am J Physiol Renal Physiol. 2017;313:F1149-F1160.
    1. Lee HJ , An J , Doo SW , et al. Improvement in spinal cord injury-induced bladder fibrosis using mesenchymal stem cell transplantation into the bladder wall. Cell Transplant. 2015;24:1253-1263.
    1. Carlson BM . The biology of long-term denervated skeletal muscle. Eur J Transl Myol. 2014;24:3293.
    1. Fry CH , Kitney DG , Paniker J , Drake MJ , Kanai A , Andersson KE . Fibrosis and the bladder, implications for function ICI-RS 2017. Neurourol Urodyn. 2018;37:S7-S12.

Publication types

Substances

LinkOut - more resources