A Genetically Determined Murine Model of Infantile Polycystic Kidney Disease

Fry, James; Koch, William E.; Jennette, J. Charles; McFarland, Eleanor C.; Fried, Floyd A.; Mandell, James

doi:10.1016/s0022-5347(17)47448-9

Cited by 64 publications

(51 citation statements)

References 7 publications

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“…4 b and e). These lateral projections appear similar to those described in early characterizations of the PKD mouse model Cys-1 cpk (34). The mutant BEC BM, in contrast to the uniform and easily visible control BM, has sections that are diffuse, indistinct, and thickened (Fig.…”

Section: Mice Lacking Xylt2supporting

confidence: 80%

Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis

Condac

Silasi‐Mansat

Kosanke

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The basic biochemical mechanisms underlying many heritable human polycystic diseases are unknown despite evidence that most cases are caused by mutations in members of several protein families, the most prominent being the polycystin gene family, whose products are found on the primary cilia, or due to mutations in posttranslational processing and transport. Inherited polycystic kidney disease, the most prevalent polycystic disease, currently affects Ϸ500,000 people in the United States. Decreases in proteoglycans (PGs) have been found in tissues and cultured cells from patients who suffer from autosomal dominant polycystic kidney disease, and this PG decrease has been hypothesized to be responsible for cystogenesis. This is possible because alterations in PG concentrations would be predicted to disrupt many homeostatic mechanisms of growth, development, and metabolism. To test this hypothesis, we have generated mice lacking xylosyltransferase 2 (XylT2), an enzyme involved in PG biosynthesis. Here we show that inactivation of XylT2 results in a substantial reduction in PGs and a phenotype characteristic of many aspects of polycystic liver and kidney disease, including biliary epithelial cysts, renal tubule dilation, organ fibrosis, and basement membrane abnormalities. Our findings demonstrate that alterations in PG concentrations can occur due to loss of XylT2, and that reduced PGs can induce cyst development.animal model ͉ extracellular matrix ͉ genetics ͉ proteoglycans ͉ cyst

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Section: Mice Lacking Xylt2supporting

confidence: 80%

Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis

Condac

Silasi‐Mansat

Kosanke

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…The cpk model was the first to be described (30,118), and as such it is probably the most extensively characterized. Mutants develop massive renal cystic disease and progressive renal insufficiency in a pattern that strongly resembles human ARPKD.…”

Section: Models Arising From Spontaneous Mutationsmentioning

confidence: 99%

“…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).…”

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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“…Many of the genes causing these disorders have been identified and characterized but none correspond to the human ARPKD gene. [13][14][15][16] Animal models generated by chemical mutagenesis also exist. 9,12,[15][16][17][18] In some of these models, only the kidneys are affected, in others in addition to renal disease, hepatic abnormalities have been described.…”

mentioning

confidence: 99%

Biliary Dysgenesis in the PCK Rat, an Orthologous Model of Autosomal Recessive Polycystic Kidney Disease

Masyuk

Huang

Masyuk

et al. 2004

The American Journal of Pathology

105

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Hepatic polycystic disease occurs alone or in combination with polycystic kidney disease (PKD). In autosomal recessive PKD (ARPKD), liver lesions are the major cause of morbidity and mortality in older patients. ARPKD is caused by a mutation to PKHD1 and the PCK rat is an orthologous model of disease. Recently, we showed that fibrocystin, Pkhd1 protein, is localized to primary cilia in rat cholangiocytes and that disruption of its ciliary expression results in biliary cystogenesis. This study describes biliary phenotype in the PCK rat using micro-computed tomography scanning and three-dimensional reconstruction, and light, scanning, and transmission microscopy. Our results show that the biliary tree undergoes extensive remodeling resulting in bile duct dilatation, focal budding, and formation of cysts that are initially connected to bile ducts, but throughout time separate from them. Progressive liver enlargement results from massive cyst formation while liver parenchymal volume remains unchanged. Cilia in cystic cells are abnormal consistent with the notion that the primary defect in ARPKD resulting in cystogenesis may be linked to ciliary dysfunction. Our results suggest that the PCK rat is a useful model for studies of biliary cystogenesis and treatment options of inherited cystic liver disease.

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A Genetically Determined Murine Model of Infantile Polycystic Kidney Disease

Cited by 64 publications

References 7 publications

Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis

Polycystic disease caused by deficiency in xylosyltransferase 2, an initiating enzyme of glycosaminoglycan biosynthesis

Murine models of polycystic kidney disease: molecular and therapeutic insights

Biliary Dysgenesis in the PCK Rat, an Orthologous Model of Autosomal Recessive Polycystic Kidney Disease

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