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A uro-protective agent with restorative actions on urethral and striated muscle morphology

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Abstract

Purpose

Aging increases oxidative stress, which can have delirious effects on smooth and striated muscle resulting in bladder dysfunction. Consequently, in women aged over 60 years, urinary incontinence (UI) is a prevalent health problem. Despite the prevalence and consequences, UI continues to be undertreated simply because there are few therapeutic options.

Methods

Here we investigated whether 8-aminoguanine (8-AG), a purine nucleoside phosphorylase (PNPase inhibitor), would restore urethra and external sphincter (EUS) muscle morphology in the aged rat. Aged (> 25 months) female Fischer 344 rats were randomized to oral treatment with 8-AG (6 weeks) or placebo, and the urethra and EUS were evaluated by electron microscopy and protein expression (western immunoblotting).

Results

Aging was associated with mitochondrial degeneration in smooth and striated muscle cells as compared to young rats. We also observed a significant increase in biomarkers such as PARP, a downstream activator of oxidative/nitrosative stress. Treatment of aged rats with 8-AG normalized all abnormalities to that of a younger state.

Conclusions

8-AG, a potent inhibitor of PNPase, reverses age-related lower urinary tract morphological and biochemical changes. Our observations support the concept that 8-AG will reverse age-induced lower urinary tract disorders such as UI. These initial findings could have therapeutic implications for the prevention and treatment of age-related UI.

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Acknowledgements

The work was supported by the National Institutes of Health (R01 AG056944, R56 AG063753 and R01 DK079307).

Funding

Funding was supported by NIH (R01 AG056944, R56 AG063753 and R01 DK079307).

Author information

Authors and Affiliations

  1. Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, A 1217 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA, 15261, USA

    Lori A. Birder & Amanda Wolf-Johnston

  2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Lori A. Birder & Edwin K. Jackson

  3. Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA

    Mara Grove-Sullivan, Donna Stoltz & Simon Watkins

  4. Division of Urology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Alan J. Wein & Diane Newman

  5. Department of Urology, Vanderbilt Medical Center, Nashville, TN, 37240, USA

    Roger R. Dmochowski

Authors
  1. Lori A. Birder
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  2. Amanda Wolf-Johnston
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  3. Alan J. Wein
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  4. Mara Grove-Sullivan
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  5. Donna Stoltz
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  6. Simon Watkins
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  7. Diane Newman
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  8. Roger R. Dmochowski
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  9. Edwin K. Jackson
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Contributions

Project development/original draft preparation: LAB and EKJ; data collection/analysis: AW-J, MG-S, DS, and SW; manuscript writing/editing: AJW, DN, and RRD.

Corresponding author

Correspondence to Lori A. Birder.

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Conflict of interest

Authors M Grove-Sullivan, D Stoltz, S Watkins and D Newman have no relevant financial or non-financial interests to disclose; patent (pending) for authors L Birder, E Jackson, A Wolf-Johnston, A Wein and R Dmochowski.

Ethical approval

The IACUC approved all procedures and conform to the Guide for the Care and Use of Laboratory Animals published by the US NIH (NIH Publication No. 85-23, revised 1996).

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Cite this article

Birder, L.A., Wolf-Johnston, A., Wein, A.J. et al. A uro-protective agent with restorative actions on urethral and striated muscle morphology. World J Urol 39, 2685–2690 (2021). https://doi.org/10.1007/s00345-020-03492-6

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  • DOI: https://doi.org/10.1007/s00345-020-03492-6

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