Urinary Bladder Dysfunction in Transgenic Sickle Cell Disease Mice.

Mário Angelo Claudino,Gilberto De Nucci,Eduardo Costa Alexandre,Fábio Henrique Da Silva,Andre Renno,Kleber Yotsumoto Fertrin,Luiz Osório Silveira Leiria,Fabiola Zakia Mónica,Fernando Ferreira Costa,Edson Antunes,Carla Fernanda Franco-Penteado,Agustin Guerrero-Hernandez

doi:10.1371/journal.pone.0133996

Mário Angelo Claudino, Gilberto De Nucci + Show 10 more

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https://doi.org/10.1371/journal.pone.0133996

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Abstract

BackgroundUrological complications associated with sickle cell disease (SCD), include nocturia, enuresis, urinary infections and urinary incontinence. However, scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms in SCD is lacking.ObjectiveThus, the aim of this study was to evaluate urinary function, in vivo and ex vivo, in the Berkeley SCD murine model (SS).MethodsUrine output was measured in metabolic cage for both wild type and SS mice (25-30 g). Bladder strips and urethra rings were dissected free and mounted in organ baths. In isolated detrusor smooth muscle (DSM), relaxant response to mirabegron and isoproterenol (1nM-10μM) and contractile response to (carbachol (CCh; 1 nM-100μM), KCl (1 mM-300mM), CaCl2 (1μM-100mM), α,β-methylene ATP (1, 3 and 10 μM) and electrical field stimulation (EFS; 1-32 Hz) were measured. Phenylephrine (Phe; 10nM-100μM) was used to evaluate the contraction mechanism in the urethra rings. Cystometry and histomorphometry were also performed in the urinary bladder.ResultsSS mice present a reduced urine output and incapacity to produce typical bladder contractions and bladder emptying (ex vivo), compared to control animals. In DSM, relaxation in response to a selective β3-adrenergic agonist (mirabegron) and to a non-selective β-adrenergic (isoproterenol) agonist were lower in SS mice. Additionally, carbachol, α, β-methylene ATP, KCl, extracellular Ca2+ and electrical-field stimulation promoted smaller bladder contractions in SS group. Urethra contraction induced by phenylephrine was markedly reduced in SS mice. Histological analyses of SS mice bladder revealed severe structural abnormalities, such as reductions in detrusor thickness and bladder volume, and cell infiltration.ConclusionsTaken together, our data demonstrate, for the first time, that SS mice display features of urinary bladder dysfunction, leading to impairment in urinary continence, which may have an important role in the pathogenesis of the enuresis and infections observed the SCD patients.

Highlights

Sickle cell disease (SCD), an inherited disorder of hemoglobin synthesis, is caused by a single nucleotide substitution (GTG for GAG) in the sixth codon of the β-globin gene
Urological complications associated with sickle cell disease (SCD), include nocturia, enuresis, urinary infections and urinary incontinence
Scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms in SCD is lacking

Summary

Introduction

Sickle cell disease (SCD), an inherited disorder of hemoglobin synthesis, is caused by a single nucleotide substitution (GTG for GAG) in the sixth codon of the β-globin gene. This mutation results in the substitution of valine for glutamic acid on the surface of the variant β-globin chain [1]. SCD-associated urological complications have been described, such as nocturia, enuresis, increased frequency of urinary infections and urinary incontinence [4]. Scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms (LUTS) in SCD patients is lacking. Urological complications associated with sickle cell disease (SCD), include nocturia, enuresis, urinary infections and urinary incontinence. Scientific evidence to ascertain the underlying cause of the lower urinary tract symptoms in SCD is lacking

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