Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease
Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular process...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/2/884 |
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| author | Sonja Djudjaj Panagiotis Kavvadas Niki Prakoura Roman D. Bülow Tiffany Migeon Sandrine Placier Christos E. Chadjichristos Peter Boor Christos Chatziantoniou |
| author_facet | Sonja Djudjaj Panagiotis Kavvadas Niki Prakoura Roman D. Bülow Tiffany Migeon Sandrine Placier Christos E. Chadjichristos Peter Boor Christos Chatziantoniou |
| author_sort | Sonja Djudjaj |
| collection | DOAJ |
| description | Background: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling. Methods: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration. Results: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis. Conclusions: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions. |
| first_indexed | 2024-03-10T01:18:02Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:18:02Z |
| publishDate | 2022-01-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-6142c25eb91847a2b416ec23fc5dc1582023-11-23T14:05:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-0123288410.3390/ijms23020884Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney DiseaseSonja Djudjaj0Panagiotis Kavvadas1Niki Prakoura2Roman D. Bülow3Tiffany Migeon4Sandrine Placier5Christos E. Chadjichristos6Peter Boor7Christos Chatziantoniou8Institute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyUnite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, FranceUnite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, FranceInstitute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyFaculty of Medicine, Sorbonne University, 75020 Paris, FranceUnite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, FranceUnite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, FranceInstitute of Pathology, University Hospital RWTH Aachen, 52074 Aachen, GermanyUnite Mixte de Recherche Scientific 1155, Institut National de la Sante et de la Recherche Medicale, Tenon Hospital, 75020 Paris, FranceBackground: Polycystic kidney disease (PKD) is a genetic disorder affecting millions of people worldwide that is characterized by fluid-filled cysts and leads to end-stage renal disease (ESRD). The hallmarks of PKD are proliferation and dedifferentiation of tubular epithelial cells, cellular processes known to be regulated by Notch signaling. Methods: We found increased Notch3 expression in human PKD and renal cell carcinoma biopsies. To obtain insight into the underlying mechanisms and the functional consequences of this abnormal expression, we developed a transgenic mouse model with conditional overexpression of the intracellular Notch3 (ICN3) domain specifically in renal tubules. We evaluated the alterations in renal function (creatininemia, BUN) and structure (cysts, fibrosis, inflammation) and measured the expression of several genes involved in Notch signaling and the mechanisms of inflammation, proliferation, dedifferentiation, fibrosis, injury, apoptosis and regeneration. Results: After one month of ICN3 overexpression, kidneys were larger with tubules grossly enlarged in diameter, with cell hypertrophy and hyperplasia, exclusively in the outer stripe of the outer medulla. After three months, mice developed numerous cysts in proximal and distal tubules. The cysts had variable sizes and were lined with a single- or multilayered, flattened, cuboid or columnar epithelium. This resulted in epithelial hyperplasia, which was observed as protrusions into the cystic lumen in some of the renal cysts. The pre-cystic and cystic epithelium showed increased expression of cytoskeletal filaments and markers of epithelial injury and dedifferentiation. Additionally, the epithelium showed increased proliferation with an aberrant orientation of the mitotic spindle. These phenotypic tubular alterations led to progressive interstitial inflammation and fibrosis. Conclusions: In summary, Notch3 signaling promoted tubular cell proliferation, the alignment of cell division, dedifferentiation and hyperplasia, leading to cystic kidney diseases and pre-neoplastic lesions.https://www.mdpi.com/1422-0067/23/2/884Notch3polycystic kidney diseaserenal cell carcinomarenal fibrosischronic kidney diseaserenal inflammation |
| spellingShingle | Sonja Djudjaj Panagiotis Kavvadas Niki Prakoura Roman D. Bülow Tiffany Migeon Sandrine Placier Christos E. Chadjichristos Peter Boor Christos Chatziantoniou Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease International Journal of Molecular Sciences Notch3 polycystic kidney disease renal cell carcinoma renal fibrosis chronic kidney disease renal inflammation |
| title | Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease |
| title_full | Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease |
| title_fullStr | Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease |
| title_full_unstemmed | Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease |
| title_short | Activation of Notch3 in Renal Tubular Cells Leads to Progressive Cystic Kidney Disease |
| title_sort | activation of notch3 in renal tubular cells leads to progressive cystic kidney disease |
| topic | Notch3 polycystic kidney disease renal cell carcinoma renal fibrosis chronic kidney disease renal inflammation |
| url | https://www.mdpi.com/1422-0067/23/2/884 |
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