Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling
Abstract Focal segmental glomerular sclerosis (FSGS) is considered an irreversible lesion in kidney disease. Here, we investigated the role of the wnt4/β-Catenin signaling pathway in FSGS lesion formation and the crosstalk between PECs and podocytes in a transgenic FSGS rat model and human primary F...
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Nature Portfolio
2025-06-01
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| Online Access: | https://doi.org/10.1038/s41598-025-04092-3 |
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| author | Eike Schwartze Eva Pfister Nicole Endlich Tim Endlich Kerstin Amann Maike Büttner-Herold Jeff Pippin Stuart J. Shankland Christoph Daniel |
| author_facet | Eike Schwartze Eva Pfister Nicole Endlich Tim Endlich Kerstin Amann Maike Büttner-Herold Jeff Pippin Stuart J. Shankland Christoph Daniel |
| author_sort | Eike Schwartze |
| collection | DOAJ |
| description | Abstract Focal segmental glomerular sclerosis (FSGS) is considered an irreversible lesion in kidney disease. Here, we investigated the role of the wnt4/β-Catenin signaling pathway in FSGS lesion formation and the crosstalk between PECs and podocytes in a transgenic FSGS rat model and human primary FSGS to explore potential sex-specific differences and therapeutic options. After model induction in rats, we observed strong podocytes loss on day 7, which was significantly higher in male than in female rats. Starting at d14, both glomerular mRNA and protein expression of Wnt4 were increased, but more pronounced in males. Wnt4 was localized to podocytes and β-Catenin to Pax8-positive lesions. The Wnt4 target gene CD44 was strongly upregulated on d7 and increased until the end of the experiment (d42). In cell culture, we confirmed that injured podocytes expressed and secreted Wnt4, which stimulated the expression of the Wnt target gene Axin2 in PECs but not in podocytes. Wnt4/β-Catenin pathway activation was confirmed in human biopsies with podocytopathic FSGS. In conclusion, the canonical Wnt/β-Catenin axis plays a critical role in the crosstalk between PECs and injured podocytes. Furthermore, sex-specific differences in podocyte injury and regeneration appear to be, at least in part, Wnt4-mediated. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-06-01 |
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| spelling | doaj-art-b5fba911d94c46eab8749ee1f6458bd92025-08-20T03:26:42ZengNature PortfolioScientific Reports2045-23222025-06-0115111510.1038/s41598-025-04092-3Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signalingEike Schwartze0Eva Pfister1Nicole Endlich2Tim Endlich3Kerstin Amann4Maike Büttner-Herold5Jeff Pippin6Stuart J. Shankland7Christoph Daniel8Department of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) and University HospitalDepartment of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) and University HospitalNipoka GmbHNipoka GmbHDepartment of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) and University HospitalDepartment of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) and University HospitalDivision of Nephrology, University of WashingtonDivision of Nephrology, University of WashingtonDepartment of Nephropathology, Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg (FAU) and University HospitalAbstract Focal segmental glomerular sclerosis (FSGS) is considered an irreversible lesion in kidney disease. Here, we investigated the role of the wnt4/β-Catenin signaling pathway in FSGS lesion formation and the crosstalk between PECs and podocytes in a transgenic FSGS rat model and human primary FSGS to explore potential sex-specific differences and therapeutic options. After model induction in rats, we observed strong podocytes loss on day 7, which was significantly higher in male than in female rats. Starting at d14, both glomerular mRNA and protein expression of Wnt4 were increased, but more pronounced in males. Wnt4 was localized to podocytes and β-Catenin to Pax8-positive lesions. The Wnt4 target gene CD44 was strongly upregulated on d7 and increased until the end of the experiment (d42). In cell culture, we confirmed that injured podocytes expressed and secreted Wnt4, which stimulated the expression of the Wnt target gene Axin2 in PECs but not in podocytes. Wnt4/β-Catenin pathway activation was confirmed in human biopsies with podocytopathic FSGS. In conclusion, the canonical Wnt/β-Catenin axis plays a critical role in the crosstalk between PECs and injured podocytes. Furthermore, sex-specific differences in podocyte injury and regeneration appear to be, at least in part, Wnt4-mediated.https://doi.org/10.1038/s41598-025-04092-3PodocyteInjuryParietal epithelial cellWnt-pathwayCrosstalk |
| spellingShingle | Eike Schwartze Eva Pfister Nicole Endlich Tim Endlich Kerstin Amann Maike Büttner-Herold Jeff Pippin Stuart J. Shankland Christoph Daniel Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling Scientific Reports Podocyte Injury Parietal epithelial cell Wnt-pathway Crosstalk |
| title | Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling |
| title_full | Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling |
| title_fullStr | Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling |
| title_full_unstemmed | Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling |
| title_short | Crosstalk of injured podocytes with parietal epithelial cells through Wnt4/β-Catenin signaling |
| title_sort | crosstalk of injured podocytes with parietal epithelial cells through wnt4 β catenin signaling |
| topic | Podocyte Injury Parietal epithelial cell Wnt-pathway Crosstalk |
| url | https://doi.org/10.1038/s41598-025-04092-3 |
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