Doxorubicin induces detrusor smooth muscle impairments through myosin dysregulation, leading to a risk of lower urinary tract dysfunction.

Document Type

Article

Publication Date

7-1-2019

Identifier

DOI: 10.1152/ajprenal.00090.2019; PMCID: PMC6692723

Abstract

Cytotoxic chemotherapy is the foundation for the treatment of the wide variety of childhood malignancies; however, these therapies are known to have a variety of deleterious side effects. One common chemotherapy used in children, doxorubicin (DOX), is well known to cause cardiotoxicity and cardiomyopathy. Recent studies have revealed that DOX impairs skeletal and smooth muscle function and contributes to fatigue and abnormal intestinal motility in patients. In this study, we tested the hypothesis that systemic DOX administration also affects detrusor smooth muscle (DSM) function in the urinary bladder, especially when administered at a young age. The effects on the DSM and bladder function were assessed in BALB/cJ mice that received six weekly intravenous injections of DOX (3 mg·kg-1·wk-1) or saline for the control group. Systemic DOX administration resulted in DSM hypertrophy, increased voiding frequency, and a significant attenuation of DSM contractility, followed by a slower relaxation compared with the control group. Gene expression analyses revealed that unlike DOX-induced cardiotoxicity, the bladders from DOX-administered animals showed no changes in oxidative stress markers; instead, downregulation of large-conductance Ca2+-activated K+ channels and altered expression of myosin light-chain kinase coincided with reduced myosin light-chain phosphorylation. These results indicate that in vivo DOX exposure caused DSM dysfunction by dysregulation of molecules involved in the detrusor contractile-relaxation mechanisms. Collectively, our findings suggest that survivors of childhood cancer treated with DOX may be at increased risk of bladder dysfunction and benefit from followup surveillance of bladder function.

Journal Title

American journal of physiology. Renal physiology

Volume

317

Issue

1

First Page

197

Last Page

197

MeSH Keywords

Age Factors; Animals; Antibiotics, Antineoplastic; Doxorubicin; Female; Hypertrophy; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Large-Conductance Calcium-Activated Potassium Channel beta Subunits; Lower Urinary Tract Symptoms; Male; Mice, Inbred BALB C; Muscle Contraction; Muscle Relaxation; Myosin Light Chains; Myosin-Light-Chain Kinase; Phosphorylation; Signal Transduction; Smooth Muscle Myosins; Time Factors; Urinary Bladder; Urinary Bladder Diseases; Urodynamics

Keywords

bladder dysfunction; detrusor; doxorubicin; myosin; smooth muscle

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