Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease

Idowu, Jessica Y.; Home, Trisha; Patel, Nisha; Magenheimer, Brenda S.; Tran, Pamela V.; Maser, Robin L.; Ward, Christopher J.; Calvet, James P.; Wallace, Darren P.; Sharma, Madhulika

doi:10.1038/s41598-018-21132-3

Cited by 35 publications

(39 citation statements)

References 46 publications

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“…Genes causing dominant and recessive forms of polycystic kidney diseases ( PKD1, GANAB, FCYT, PKD2, DNAJB11 , and DZIP1L) had a good coverage in the ES and no pathogenic variants were identified. Disruption of NOTCH pathway during development resulted in proximal tubular cysts and, and its overexpression correlated to rapidly growing cysts in kidneys of autosomal recessive and autosomal dominant polycystic kidney disease mouse models (Idowu et al, ). Nevertheless, the description of further individuals with LMS is required to conclude whether inner ear malformation and cystic kidney are indeed features of LMS.…”

Section: Discussionmentioning

confidence: 99%

Expansion of the phenotype of lateral meningocele syndrome

Cappuccio

Apuzzo

Alagia

et al. 2020

American J of Med Genetics Pt A

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Lateral meningocele syndrome (LMS) is due to specific pathogenic variants in the last exon of NOTCH3 gene. Besides the lateral meningoceles, this condition presents with dysmorphic features, short stature, congenital heart defects, and feeding difficulties.Here, we report a girl with neurosensorial hearing loss, severe gastroesophageal reflux disease, congenital heart defects, multiple renal cysts, kyphosis and left-convex scoliosis, dysmorphic features, and mild developmental delay. Exome sequencing detected the previously unreported de novo loss-of-function variant in exon 33 of NOTCH3 p.(Lys2137fs). Following the identification of the gene defect, MRI of the brain and spine revealed temporal encephaloceles, inner ears anomalies, multiple spinal lateral meningoceles, and intra-and extra-dural arachnoid spinal cysts. This case illustrates the power of reverse phenotyping to establish clinical diagnosis and expands the spectrum of clinical manifestations related to LMS to include inner ear abnormalities and multi-cystic kidney disease. K E Y W O R D S encephalocele, lateral meningocele syndrome, NOTCH3

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Section: Discussionmentioning

confidence: 99%

Expansion of the phenotype of lateral meningocele syndrome

Cappuccio

Apuzzo

Alagia

et al. 2020

American J of Med Genetics Pt A

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“…We have previously shown equivalent fold reduction in cyst size with 50 µM DAPT (N-(N-(3,5-Difluorophenacetyl)-S phenylglycine t-butyl ester) treatment 31 .…”

Section: Cpx-o Inhibits Cyst Formation Of Adpkd Cells In 3d Cyst Assaysmentioning

confidence: 99%

“…We have previously shown that the Notch3 signaling pathway was activated in human ADPKD cyst lining cells 31…”

Section: Protection Mediated By Cpx-o Does Not Involve Notch Pathway mentioning

confidence: 99%

“…Tissues (fresh or frozen) were chopped in pieces and homogenized using a Dounce homogenizer. For both cells and tissues, RIPA lysis buffer (50 mM Tris HCl pH7.5, 137 mM NaCl,1% IGEPAL, 2 mM EDTA) with protease inhibitors (Protease inhibitor cocktail, Fisher Scientific, Pittsburg, PA) was used 31 .…”

Section: Immunocytochemistry (Icc)mentioning

confidence: 99%

“…PC1 and PC2 function in the cilia and appear to be important in the regulation of intracellular Ca 2+ .Decreased intracellular Ca 2+ levels in ADPKD cells in combination with activation of adenylate cyclase and accumulation of cAMP lead to increased proliferation and fluid secretion and contribute to enlargement of cysts [3][4][5][6] . Many signaling pathways have been shown to be deregulated in response to loss of function mutations in PKD 2,3,7,8 .…”

Section: Introductionmentioning

confidence: 99%

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Ciclopirox Olamine Induces Ferritinophagy and Ameliorates Disease Progression in Polycystic Kidney Disease

Radadiya¹,

Puri²,

Magenheimer³

et al. 2020

Preprint

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Despite the recent launch of Tolvaptan, the search for safer polycystic kidney disease (PKD) drugs continues. Ciclopirox, as the free acid (CPX) and its olamine salt (CPX-O) , are contained in number of commercially available topical antifungal agents. CPX is reported in the literature to possess anticancer activity in number of solid tumor cancers and hematological malignancy by several proposed mechanisms of action including chelation of iron and inhibition of iron dependent enzymes. Here, we show that CPX-O inhibited in vitro cystogenesis of primary human cyst epithelial cells cultured in 3D collagen matrix. To determine if CPX-O inhibits PKD progression, we treated PKD mice with a low dose of 10 mg/kg CPX-O by daily intraperitoneal injections from day 21 to day 49 post- partum. CPX-O reduced the kidney to body weight ratio of the PKD mice. This was associated with decreased cell proliferation decrease cystic area and improved renal function. We found that ferritin levels were significantly elevated in cystic kidneys of PKD mice, and that CPX-O treatment reduced renal ferritin levels and increased ferritinophagy marker, NCOA4. Our data suggest that CPX-O dose dependently induces ferritin degradation via ferritinophagy which is associated with decreased cyst growth and disease progression in PKD mice. Most importantly these data indicate that CPX-O, a drug used to treat skin infections and currently in clinical trials for cancer, has the potential to treat ADPKD.

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IFT‐A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease

Wang

Pottorf

Wang

et al. 2021

The Journal of Pathology

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Polycystic liver disease (PLD) is characterized by the growth of numerous biliary cysts and presents in patients with autosomal dominant polycystic kidney disease (ADPKD), causing significant morbidity. Interestingly, deletion of intraflagellar transport‐B (IFT‐B) complex genes in adult mouse models of ADPKD attenuates the severity of PKD and PLD. Here we examine the role of deletion of an IFT‐A gene, Thm1, in PLD of juvenile and adult Pkd2 conditional knockout mice. Perinatal deletion of Thm1 resulted in disorganized and expanded biliary regions, biliary fibrosis, increased serum bile acids, and a shortened primary cilium on cytokeratin 19+ (CK19+) epithelial cells. In contrast, perinatal deletion of Pkd2 caused PLD, with multiple CK19+ epithelial cell‐lined cysts, fibrosis, lengthened primary cilia, and increased Notch and ERK signaling. Perinatal deletion of Thm1 in Pkd2 conditional knockout mice increased hepatomegaly, liver necrosis, as well as serum bilirubin and bile acid levels, indicating enhanced liver disease severity. In contrast to effects in the developing liver, deletion of Thm1 alone in adult mice did not cause a biliary phenotype. Combined deletion of Pkd2 and Thm1 caused variable hepatic cystogenesis at 4 months of age, but differences in hepatic cystogenesis between Pkd2‐ and Pkd2;Thm1 knockout mice were not observed by 6 months of age. Similar to juvenile PLD, Notch and ERK signaling were increased in adult Pkd2 conditional knockout cyst‐lining epithelial cells. Taken together, Thm1 is required for biliary tract development, and proper biliary development restricts PLD severity. Unlike IFT‐B genes, Thm1 does not markedly attenuate hepatic cystogenesis, suggesting differences in regulation of signaling and cystogenic processes in the liver by IFT‐B and ‐A. Notably, increased Notch signaling in cyst‐lining epithelial cells may indicate that aberrant activation of this pathway promotes hepatic cystogenesis, presenting as a novel potential therapeutic target. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Aberrant Regulation of Notch3 Signaling Pathway in Polycystic Kidney Disease

Cited by 35 publications

References 46 publications

Expansion of the phenotype of lateral meningocele syndrome

Expansion of the phenotype of lateral meningocele syndrome

Ciclopirox Olamine Induces Ferritinophagy and Ameliorates Disease Progression in Polycystic Kidney Disease

IFT‐A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease

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