BECLIN1 Is Essential for Podocyte Secretory Pathways Mediating VEGF Secretion and Podocyte-Endothelial Crosstalk
Vascular endothelial growth factor A (VEGFA) secretion from podocytes is crucial for maintaining endothelial integrity within the glomerular filtration barrier. However, until now, the molecular mechanisms underlying podocyte secretory function remained unclear. Through podocyte-specific deletion of...
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| Format: | Article |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3825 |
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| author | Tillmann Bork Wei Liang Oliver Kretz Simon Lagies Kosuke Yamahara Camila Hernando-Erhard Martin Helmstädter Christoph Schell Bernd Kammerer Tobias B. Huber |
| author_facet | Tillmann Bork Wei Liang Oliver Kretz Simon Lagies Kosuke Yamahara Camila Hernando-Erhard Martin Helmstädter Christoph Schell Bernd Kammerer Tobias B. Huber |
| author_sort | Tillmann Bork |
| collection | DOAJ |
| description | Vascular endothelial growth factor A (VEGFA) secretion from podocytes is crucial for maintaining endothelial integrity within the glomerular filtration barrier. However, until now, the molecular mechanisms underlying podocyte secretory function remained unclear. Through podocyte-specific deletion of BECLIN1 (<i>ATG6</i> or <i>Becn1</i>), a key protein in autophagy initiation, we identified a major role for this molecule in anterograde Golgi trafficking. The <i>Becn1</i>-deficient podocytes displayed aberrant vesicle formation in the <i>trans-</i>Golgi network (TGN), leading to dramatic vesicle accumulation and complex disrupted patterns of intracellular vesicle trafficking and membrane dynamics. Phenotypically, podocyte-specific deletion of <i>Becn1</i> resulted in early-onset glomerulosclerosis, which rapidly progressed and dramatically reduced mouse life span. Further, in vivo and in vitro studies clearly showed that VEGFA secretion, and thereby endothelial integrity, greatly depended on BECLIN1 availability and function. Being the first to demonstrate the importance of a secretory pathway for podocyte integrity and function, we identified BECLIN1 as a key component in this complex cellular process. Functionally, by promoting VEGFA secretion, a specific secretory pathway emerged as an essential component for the podocyte-endothelial crosstalk that maintains the glomerular filtration barrier. |
| first_indexed | 2024-03-09T11:45:55Z |
| format | Article |
| id | doaj.art-d72f3f7278814c8eaa1ba223e18a1efc |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:45:55Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d72f3f7278814c8eaa1ba223e18a1efc2023-11-30T23:22:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01237382510.3390/ijms23073825BECLIN1 Is Essential for Podocyte Secretory Pathways Mediating VEGF Secretion and Podocyte-Endothelial CrosstalkTillmann Bork0Wei Liang1Oliver Kretz2Simon Lagies3Kosuke Yamahara4Camila Hernando-Erhard5Martin Helmstädter6Christoph Schell7Bernd Kammerer8Tobias B. Huber9Department of Medicine IV, Faculty of Medicine, University of Freiburg, 79106 Freiburg, GermanyDivision of Nephrology, Renmin Hospital of Wuhan University, Wuhan 430060, ChinaIII Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyCentre for Integrative Signalling Analysis, University of Freiburg, 79104 Freiburg, GermanyDepartment of Medicine, Shiga University of Medical Science, Otsu 520-2192, JapanDepartment of Medicine IV, Faculty of Medicine, University of Freiburg, 79106 Freiburg, GermanyDepartment of Medicine IV, Faculty of Medicine, University of Freiburg, 79106 Freiburg, GermanyInstitute of Surgical Pathology, Faculty of Medicine, University of Freiburg, 79106 Freiburg, GermanyCentre for Integrative Signalling Analysis, University of Freiburg, 79104 Freiburg, GermanyIII Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, GermanyVascular endothelial growth factor A (VEGFA) secretion from podocytes is crucial for maintaining endothelial integrity within the glomerular filtration barrier. However, until now, the molecular mechanisms underlying podocyte secretory function remained unclear. Through podocyte-specific deletion of BECLIN1 (<i>ATG6</i> or <i>Becn1</i>), a key protein in autophagy initiation, we identified a major role for this molecule in anterograde Golgi trafficking. The <i>Becn1</i>-deficient podocytes displayed aberrant vesicle formation in the <i>trans-</i>Golgi network (TGN), leading to dramatic vesicle accumulation and complex disrupted patterns of intracellular vesicle trafficking and membrane dynamics. Phenotypically, podocyte-specific deletion of <i>Becn1</i> resulted in early-onset glomerulosclerosis, which rapidly progressed and dramatically reduced mouse life span. Further, in vivo and in vitro studies clearly showed that VEGFA secretion, and thereby endothelial integrity, greatly depended on BECLIN1 availability and function. Being the first to demonstrate the importance of a secretory pathway for podocyte integrity and function, we identified BECLIN1 as a key component in this complex cellular process. Functionally, by promoting VEGFA secretion, a specific secretory pathway emerged as an essential component for the podocyte-endothelial crosstalk that maintains the glomerular filtration barrier.https://www.mdpi.com/1422-0067/23/7/3825podocyteBECLIN1autophagysecretory pathwayGolgi networkVEGF |
| spellingShingle | Tillmann Bork Wei Liang Oliver Kretz Simon Lagies Kosuke Yamahara Camila Hernando-Erhard Martin Helmstädter Christoph Schell Bernd Kammerer Tobias B. Huber BECLIN1 Is Essential for Podocyte Secretory Pathways Mediating VEGF Secretion and Podocyte-Endothelial Crosstalk International Journal of Molecular Sciences podocyte BECLIN1 autophagy secretory pathway Golgi network VEGF |
| title | BECLIN1 Is Essential for Podocyte Secretory Pathways Mediating VEGF Secretion and Podocyte-Endothelial Crosstalk |
| title_full | BECLIN1 Is Essential for Podocyte Secretory Pathways Mediating VEGF Secretion and Podocyte-Endothelial Crosstalk |
| title_fullStr | BECLIN1 Is Essential for Podocyte Secretory Pathways Mediating VEGF Secretion and Podocyte-Endothelial Crosstalk |
| title_full_unstemmed | BECLIN1 Is Essential for Podocyte Secretory Pathways Mediating VEGF Secretion and Podocyte-Endothelial Crosstalk |
| title_short | BECLIN1 Is Essential for Podocyte Secretory Pathways Mediating VEGF Secretion and Podocyte-Endothelial Crosstalk |
| title_sort | beclin1 is essential for podocyte secretory pathways mediating vegf secretion and podocyte endothelial crosstalk |
| topic | podocyte BECLIN1 autophagy secretory pathway Golgi network VEGF |
| url | https://www.mdpi.com/1422-0067/23/7/3825 |
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