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

McHugh KM - Pediatr. Nephrol. (2013)

Bottom Line: The direct link between obstructed urine flow and abnormal renal development and subsequent dysfunction represents a central paradigm of urogenital pathogenesis that has far-reaching clinical implications.Studies in our laboratory have characterized a unique mutant mouse line that develops in utero megabladder, variable hydronephrosis, and progressive renal failure.Recent studies have begun to shed light on the genetic etiology of mgb (-/-) mice as well as the molecular pathways controlling disease progression in these animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics and Division of Anatomy, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA, Kirk.McHugh@nationwidechildrens.org.

ABSTRACT
Congenital obstructive nephropathy remains one of the leading causes of chronic renal failure in children. The direct link between obstructed urine flow and abnormal renal development and subsequent dysfunction represents a central paradigm of urogenital pathogenesis that has far-reaching clinical implications. Even so, a number of diagnostic, prognostic, and therapeutic quandaries still exist in the management of congenital obstructive nephropathy. Studies in our laboratory have characterized a unique mutant mouse line that develops in utero megabladder, variable hydronephrosis, and progressive renal failure. Megabladder mice represent a valuable functional model for the study of congenital obstructive nephropathy. Recent studies have begun to shed light on the genetic etiology of mgb (-/-) mice as well as the molecular pathways controlling disease progression in these animals.

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Postnatal day 2 outflow tracts a, b without and c, d with methylene blue injection showing patent ductus arteriosus in the mgb compound heterozygote (a, c; arrow) versus ligamentum arteriosum in the control (b, d; arrow). Left carotid artery (L Carotid), innominate (brachiocephalic) artery (Innominate), ascending aorta (AAo), and pulmonary trunk (PT)
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Fig1: Postnatal day 2 outflow tracts a, b without and c, d with methylene blue injection showing patent ductus arteriosus in the mgb compound heterozygote (a, c; arrow) versus ligamentum arteriosum in the control (b, d; arrow). Left carotid artery (L Carotid), innominate (brachiocephalic) artery (Innominate), ascending aorta (AAo), and pulmonary trunk (PT)

Mentions: Recent studies indicate that further reduction in myocardin expression through genetic manipulation not only recapitulates the mgb−/− bladder phenotype, but also results in the appearance of a second genetic defect—patent ductus arteriosus (Fig. 1). Although a direct link between bladder smooth muscle development and patent ductus arteriosus may not be self-evident, a review of their developmental origins identifies a common cellular lineage. During cardiac development, the outflow tract receives a critical contribution from the cranial neural crest associated with the branchial arches. These cells seed the developing cardiac outflow tract and its associated vessels providing them with the smooth muscle progenitors necessary for normal vascular development. Even though bladder smooth muscle is principally derived from splanchnic mesenchyme (mesoderm) and not neural crest (neuroectoderm), the smooth muscle differentiation program in both cell types is controlled by myocardin expression. Morphological analysis confirmed a lack of smooth muscle cells within the ductus arteriosus of these animals (unpublished results). Therefore, the appearance of patent ductus arteriosus in genetically altered mgb mice represents a structural defect in the target cell type necessary for normal physiological closure.Fig. 1


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

McHugh KM - Pediatr. Nephrol. (2013)

Postnatal day 2 outflow tracts a, b without and c, d with methylene blue injection showing patent ductus arteriosus in the mgb compound heterozygote (a, c; arrow) versus ligamentum arteriosum in the control (b, d; arrow). Left carotid artery (L Carotid), innominate (brachiocephalic) artery (Innominate), ascending aorta (AAo), and pulmonary trunk (PT)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3928515&req=5

Fig1: Postnatal day 2 outflow tracts a, b without and c, d with methylene blue injection showing patent ductus arteriosus in the mgb compound heterozygote (a, c; arrow) versus ligamentum arteriosum in the control (b, d; arrow). Left carotid artery (L Carotid), innominate (brachiocephalic) artery (Innominate), ascending aorta (AAo), and pulmonary trunk (PT)
Mentions: Recent studies indicate that further reduction in myocardin expression through genetic manipulation not only recapitulates the mgb−/− bladder phenotype, but also results in the appearance of a second genetic defect—patent ductus arteriosus (Fig. 1). Although a direct link between bladder smooth muscle development and patent ductus arteriosus may not be self-evident, a review of their developmental origins identifies a common cellular lineage. During cardiac development, the outflow tract receives a critical contribution from the cranial neural crest associated with the branchial arches. These cells seed the developing cardiac outflow tract and its associated vessels providing them with the smooth muscle progenitors necessary for normal vascular development. Even though bladder smooth muscle is principally derived from splanchnic mesenchyme (mesoderm) and not neural crest (neuroectoderm), the smooth muscle differentiation program in both cell types is controlled by myocardin expression. Morphological analysis confirmed a lack of smooth muscle cells within the ductus arteriosus of these animals (unpublished results). Therefore, the appearance of patent ductus arteriosus in genetically altered mgb mice represents a structural defect in the target cell type necessary for normal physiological closure.Fig. 1

Bottom Line: The direct link between obstructed urine flow and abnormal renal development and subsequent dysfunction represents a central paradigm of urogenital pathogenesis that has far-reaching clinical implications.Studies in our laboratory have characterized a unique mutant mouse line that develops in utero megabladder, variable hydronephrosis, and progressive renal failure.Recent studies have begun to shed light on the genetic etiology of mgb (-/-) mice as well as the molecular pathways controlling disease progression in these animals.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics and Division of Anatomy, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA, Kirk.McHugh@nationwidechildrens.org.

ABSTRACT
Congenital obstructive nephropathy remains one of the leading causes of chronic renal failure in children. The direct link between obstructed urine flow and abnormal renal development and subsequent dysfunction represents a central paradigm of urogenital pathogenesis that has far-reaching clinical implications. Even so, a number of diagnostic, prognostic, and therapeutic quandaries still exist in the management of congenital obstructive nephropathy. Studies in our laboratory have characterized a unique mutant mouse line that develops in utero megabladder, variable hydronephrosis, and progressive renal failure. Megabladder mice represent a valuable functional model for the study of congenital obstructive nephropathy. Recent studies have begun to shed light on the genetic etiology of mgb (-/-) mice as well as the molecular pathways controlling disease progression in these animals.

Show MeSH
Related in: MedlinePlus