Megabladder mouse model of congenital obstructive nephropathy: genetic etiology and renal adaptation

McHugh, Kirk M.

doi:10.1007/s00467-013-2658-6

Cited by 7 publications

(8 citation statements)

References 37 publications

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“…A more bladder-specific disruption has been seen with “megabladder” mice (Singh et al, 2007 ; McHugh, 2014 ), a phenotype caused by randomly inserting a transgene into chromosome 16 that subsequently, along with a portion of chromosome 16, translocated to chromosome 11 downstream of myocardin. Profound changes, including severe distension and thinning of bladder wall were reported in utero , with the bladder almost completely lacking detrusor muscle; less dramatic changes occur in lamina propria and urothelium.…”

Section: Genetic Models Of Bladder Dysfunctionmentioning

confidence: 99%

Developing a functional urinary bladder: a neuronal context

Keast

Smith-Anttila

Osborne

2015

Front. Cell Dev. Biol.

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The development of organs occurs in parallel with the formation of their nerve supply. The innervation of pelvic organs (lower urinary tract, hindgut, and sexual organs) is complex and we know remarkably little about the mechanisms that form these neural pathways. The goal of this short review is to use the urinary bladder as an example to stimulate interest in this question. The bladder requires a healthy mature nervous system to store urine and release it at behaviorally appropriate times. Understanding the mechanisms underlying the construction of these neural circuits is not only relevant to defining the basis of developmental problems but may also suggest strategies to restore connectivity and function following injury or disease in adults. The bladder nerve supply comprises multiple classes of sensory, and parasympathetic or sympathetic autonomic effector (motor) neurons. First, we define the developmental endpoint by describing this circuitry in adult rodents. Next we discuss the innervation of the developing bladder, identifying challenges posed by this area of research. Last we provide examples of genetically modified mice with bladder dysfunction and suggest potential neural contributors to this state.

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Section: Genetic Models Of Bladder Dysfunctionmentioning

confidence: 99%

Developing a functional urinary bladder: a neuronal context

Keast

Smith-Anttila

Osborne

2015

Front. Cell Dev. Biol.

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“…In contrast to human kidney development, nephrogenesis is still active at birth in the mouse, continuing until 7-10 days postnatally. In mgb-/- mice, bladder smooth muscle development is severely impaired (8). As a result of impaired antegrade urine flow, hydroureteronephrosis develops with variable timing and severity, arising as early as E17.5 and often progressing throughout the lifetime of the animal (5, 6).…”

Section: Discussionmentioning

confidence: 99%

“…The present study supports a role of miR-205 in regulation of urothelial differentiation, providing a potential mechanism for these changes. In our revised model, worsening hydronephrosis induces expression of miR-205, which may mediate an adaptive response (8) that alters or reactivates urothelial differentiation pathways. Although these changes may have some deleterious effects due to altered urothelial function and permeability, they may be critical in initiating an organ-protective response during pathogenic insult to the kidney.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously characterized the pathogenesis of CON in the megabladder (mgb) mouse (5, 6). The mgb mouse is a unique transgene-induced mutant mouse line in which impaired bladder emptying and hydronephrosis are prominent features (7, 8). The CKD course followed by male mgb-/- mice, from in utero voiding impairment to ESRD and death at sexual maturation, provides an excellent opportunity to investigate the molecular and cellular factors that drive the onset and progression of CON.…”

Section: Introductionmentioning

confidence: 99%

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Renal epithelial miR-205 expression correlates with disease severity in a mouse model of congenital obstructive nephropathy

Wilhide

Feller

et al. 2016

Pediatr Res

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Background Congenital obstructive nephropathy (CON) is a leading cause of pediatric chronic kidney disease (CKD). Despite optimal surgical and medical care, there is a high rate of CKD progression. Better understanding of molecular and cellular changes is needed to facilitate development of improved biomarkers and novel therapeutic approaches in CON. Methods The megabladder (mgb) mouse is an animal model of CKD with impaired bladder emptying, hydronephrosis, and progressive renal injury. In this study, we characterize a particular microRNA, miR-205, whose expression changes with the degree of hydronephrosis in the mgb-/- kidney. Results Expression of miR-205 is progressively increased in the adult mgb-/-mouse with worsening severity of hydronephrosis. miR-205 expression is correlated with altered expression of cytokeratins and uroplakins, which are markers of cellular differentiation in urothelium. We describe the spatial pattern of miR-205 expression, including increased expression in renal urothelium and novel miR-205 expression in medullary collecting duct epithelium in the congenitally obstructed kidney. Conclusion miR-205 is increased with severity of congenital obstructive nephropathy and CKD in the mgb-/- mouse, and may regulate urothelial differentiation.

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“…For example, altered apical plaque composition in severely hydronephrotic mgb −/− kidneys may increase susceptibility to infection, since specific Upk proteins have been postulated to function as bacterial binding sites [8, 20]. The subsequent development of pyelonephritis could serve as a second pathogenic ‘hit’ that tips the balance away from renal repair to permanent renal damage and altered renal function [31]. In fact, this precise scenario occurs in mgb −/− mice that develop pyelonephritis [32].…”

Section: Urothelium and Pathogenesismentioning

confidence: 99%

Role of renal urothelium in the development and progression of kidney disease

Carpenter

McHugh

2016

Pediatr Nephrol

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The clinical and financial impact of chronic kidney disease (CKD) is significant, while the progression and prognosis of CKD is variable and often poor. Studies using the megabladder (mgb−/−) model of CKD have shown that renal urothelium plays a key role in modulating the early injury responses following the development of congenital obstruction. The aim of this review is to examine the role that urothelium has in normal urinary tract development and pathogenesis. We discuss normal morphology of renal urothelium and then examine the role that uroplakins (Upks) play in its development. Histologic, biochemical and molecular characterization of Upk1bRFP/RFP mice indicated Upk1b expression is essential for normal urinary tract development, apical plaque/AUM formation and differentiation and functional integrity of the renal urothelium. Our studies provide the first evidence Upk1b is directly associated with the development of congenital anomalies of the urinary tract (CAKUT), spontaneous age-dependent hydronephrosis and dysplastic urothelia. These observations demonstrate the importance of proper urothelial differentiation in the normal development and pathogenesis of the urinary tract, and provide a unique working model to test the hypothesis that the complex etiology associated with CKD is dependent upon predetermined genetic susceptibilities that establish pathogenic thresholds for disease initiation and progression.

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Megabladder mouse model of congenital obstructive nephropathy: genetic etiology and renal adaptation

Cited by 7 publications

References 37 publications

Developing a functional urinary bladder: a neuronal context

Developing a functional urinary bladder: a neuronal context

Renal epithelial miR-205 expression correlates with disease severity in a mouse model of congenital obstructive nephropathy

Role of renal urothelium in the development and progression of kidney disease

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