Murine autosomal recessive polycystic kidney disease with multiorgan involvement induced by the cpk gene

Gattone, Vincent H.; MacNaughton, Kathleen A.; Kraybill, Amy L.

doi:10.1002/(sici)1097-0185(199607)245:3<488::aid-ar5>3.3.co;2-m

Cited by 19 publications

(36 citation statements)

References 13 publications

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“…These mutants die from a rapid progressive renal insufficiency and do not develop biliary ductal plate malformations. 6,7 PKD associated with a hypomorphic allele of the Tg737 polaris gene also closely resembles the clinical features of human ARPKD. The (Tg737/orpk) mutants develop renal cysts, biliary-dysgenesis, pancreatic cysts, and skeletal defects.…”

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confidence: 74%

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ADP-Ribosylation Factor-Like 3 Is Involved in Kidney and Photoreceptor Development

Schrick

Vogel

Abuin

et al. 2006

The American Journal of Pathology

140

114

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ADP-ribosylation factor-like 3 (Arl3) is a member of a small subfamily of G-proteins involved in membraneassociated vesicular and intracellular trafficking processes. Genetic studies in Leishmania have shown that the Arl3 homolog is essential for flagellum biogenesis. Mutations in a related human family member, Arl6, result in Bardet-Biedl syndrome in humans, which is characterized by genital, renal, and retinal abnormalities, obesity, and learning deficits. As part of our largescale phenotypic screen, mice deficient for the Arl3 gene were generated and analyzed. Arl3 (؊/؊) mice were born at a sub-Mendelian ratio, were small and sickly, and had markedly swollen abdomens. These mutants failed to thrive, and all died by 3 weeks of age. The (؊/؊) mice exhibited abnormal development of renal, hepatic, and pancreatic epithelial tubule structures, which is characteristic of the renal-hepatic-pancreatic dysplasia found in autosomal recessive polycystic kidney disease. Absence of Arl3 was associated with abnormal epithelial cell proliferation and cyst formation. Moreover, mice lacking Arl3 exhibited photoreceptor degeneration as early as postnatal day 14. These results are the first to implicate Arl3 in a ciliary disease affecting the kidney, biliary tract, pancreas, and retina.

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confidence: 74%

“…[3][4][5][6][7] These models have proven very useful in elucidating the roles of altered cell proliferation, cell differentiation, extracellular matrix composition, ionic transport, and oncogene expression in the development of PKD. The best characterized models are the congenital PKD mouse (cpk) 3 and the Oak Ridge PKD mouse (Tg737/orpk).…”

mentioning

confidence: 99%

ADP-Ribosylation Factor-Like 3 Is Involved in Kidney and Photoreceptor Development

Schrick

Vogel

Abuin

et al. 2006

The American Journal of Pathology

140

114

View full text Add to dashboard Cite

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“…43,44,78 In many cases (such as polycystin-1, polycystin-2, fibrocystin, inversin, and cystin), the affected genes encode proteins that localize to renal cilia, suggesting that cilia dysfunction is a key factor in the pancreatic pathologies of these mutant mice. 24,34,77,79 In contrast to Tg737, the loss of these proteins does not affect cilia assembly but more likely alters some aspect of their signaling activity.…”

Section: Presence Of Cilia In the Pancreas And Cilia Defects In Tg737mentioning

confidence: 99%

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

Zhang

Davenport

Croyle

et al. 2005

Laboratory Investigation

100

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While relatively ignored for years as vestigial, cilia have recently become the focus of intense interest as organelles that result in severe pathologies when disrupted. Here, we further establish a connection between cilia dysfunction and disease by showing that loss of polaris (Tg737), an intraflagellar transport (IFT) protein required for ciliogenesis, causes abnormalities in the exocrine and endocrine pancreas of the Tg737 orpk mouse. Pathology is evident late in gestation as dilatations of the pancreatic ducts that continue to expand postnatally. Shortly after birth, the acini become disorganized, undergo apoptosis, and are largely ablated in late stage pathology. In addition, serum amylase levels are elevated and carboxypeptidase is abnormally activated within the pancreas. Ultrastructural analysis reveals that the acini undergo extensive vacuolization and have numerous 'halo-granules' similar to that seen in induced models of pancreatitis resulting from duct obstruction. Intriguingly, although the acini are severely affected in Tg737 orpk mutants, cilia and Tg737 expression are restricted to the ducts and islets and are not detected on acinar cells. Analysis of the endocrine pancreas in Tg737 orpk mutants revealed normal differentiation and distribution of cell types in the islets. However, after fasting, mutant blood glucose levels are significantly lower than controls and when challenged in glucose tolerance tests, Tg737 orpk mutants exhibited defects in glucose uptake. These findings are interesting in light of the recently proposed role for polaris, the protein encoded by the Tg737 gene, in the hedgehog pathway and hedgehog signaling in insulin production and glucose homeostasis.

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“…The ductal plate malformation (DPM), the biliary abnormality described in human ARPKD, is not penetrant in B6-cpk/cpk mice (30). However, when cpk is expressed on other genetic backgrounds, e.g., Mus mus castaneus (CAST/Ei), DBA/2J, BALB/c, or CD1, cpk mutants have renal collecting duct cysts as well as biliary and pancreatic duct abnormalities (38,40,50,125). B6 heterozygotes do not express disease, whereas aged F1 heterozygotes from crosses with the DBA/2J and BALB/c strains can develop biliary cysts.…”

Section: Models Arising From Spontaneous Mutationsmentioning

confidence: 99%

Murine models of polycystic kidney disease: molecular and therapeutic insights

Guay‐Woodford

2003

American Journal of Physiology-Renal Physiology

176

160

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Guay-Woodford, Lisa M. Murine models of polycystic kidney disease: molecular and therapeutic insights. Am J Physiol Renal Physiol 285: F1034-F1049, 2003 10.1152/ajprenal. 00195.2003.-Numerous murine (mouse and rat) models of polycystic kidney disease (PKD) have been described in which the mutant phenotype results from a spontaneous mutation or engineering via chemical mutagenesis, transgenic technologies, or gene-specific targeting in mouse orthologs of human PKD genes. These murine phenotypes closely resemble human PKD, with common abnormalities observed in tubular epithelia, the interstitial compartment, and the extracellular matrix of cystic kidneys. In both human and murine PKD, genetic background appears to modulate the renal cystic phenotype. In murine models, these putative modifying effects have been dissected into discrete factors called quantitative trait loci and genetically mapped. Several lines of experimental evidence support the hypothesis that PKD genes and their modifiers may define pathways involved in cystogenesis and PKD progression. Among the various pathway abnormalities described in murine PKD, recent provocative data indicate that structural and/or functional defects in the primary apical cilia of tubular epithelia may play a key role in PKD pathogenesis. This review describes the most widely studied murine models; highlights the data regarding specific gene defects and genetic modifiers; summarizes the data from these models that have advanced our understanding of PKD pathogenesis; and examines the effect of various therapeutic interventions in murine PKD.autosomal dominant polycystic kidney disease; autosomal recessive polycystic kidney disease; polycystic kidney disease quantitative trait loci; polycystic kidney disease therapeutics RENAL TUBULAR CYSTS DEVELOP in several inherited human disorders. Among these, the polycystic kidney diseases (PKD) are one of the leading causes of endstage renal disease in children and adults (31). Autosomal dominant polycystic kidney disease (ADPKD) occurs in 1:1,000 individuals, primarily as the result of mutations in one of two genes, PKD1 or PKD2 (81,(150)(151)(152). In comparison, autosomal recessive polycystic kidney disease (ARPKD) is much less frequent (1: 20,000 live births) and results primarily from mutations in a single gene, PKHD1 (107, 162).The principal pathological manifestations in PKD involve 1) the formation of epithelial-lined cysts throughout the nephron in ADPKD and predominantly in the collecting duct in ARPKD; 2) alterations in cell polarity; and 3) changes in extracellular matrix composition. In addition to the renal cystic disease, ADPKD is associated with cyst formation in other epithelial organs, most notably the liver and pancreas, as well as connective tissue defects, such as intracranial aneurysms, aortic dissection, cardiac valve abnormalities, and abdominal wall hernias (116). In comparison, the ARPKD phenotype is expressed almost exclusively in the kidney and liver, with the latter lesion involving biliary dysgenesis a...

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Murine autosomal recessive polycystic kidney disease with multiorgan involvement induced by the cpk gene

Cited by 19 publications

References 13 publications

ADP-Ribosylation Factor-Like 3 Is Involved in Kidney and Photoreceptor Development

ADP-Ribosylation Factor-Like 3 Is Involved in Kidney and Photoreceptor Development

Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737 mutant mice

Murine models of polycystic kidney disease: molecular and therapeutic insights

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