Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury
The kidney glomerular filtration barrier (GFB) is enriched with heparan sulfate (HS) proteoglycans, which contribute to its permselectivity. The endoglycosidase heparanase cleaves HS and hence appears to be involved in the pathogenesis of kidney injury and glomerulonephritis. We have recently report...
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MDPI AG
2022-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/20/12691 |
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| author | Hanan Abu-Tayeh Suleiman Shereen Said Haya Ali Saleh Aviva Gamliel-Lazarovich Eyas Haddad Irina Minkov Yaniv Zohar Neta Ilan Israel Vlodavsky Zaid Abassi Suheir Assady |
| author_facet | Hanan Abu-Tayeh Suleiman Shereen Said Haya Ali Saleh Aviva Gamliel-Lazarovich Eyas Haddad Irina Minkov Yaniv Zohar Neta Ilan Israel Vlodavsky Zaid Abassi Suheir Assady |
| author_sort | Hanan Abu-Tayeh Suleiman |
| collection | DOAJ |
| description | The kidney glomerular filtration barrier (GFB) is enriched with heparan sulfate (HS) proteoglycans, which contribute to its permselectivity. The endoglycosidase heparanase cleaves HS and hence appears to be involved in the pathogenesis of kidney injury and glomerulonephritis. We have recently reported, nonetheless, that heparanase overexpression preserved glomerular structure and kidney function in an experimental model of Adriamycin-induced nephropathy. To elucidate mechanisms underlying heparanase function in podocytes—key GFB cells, we utilized a human podocyte cell line and transgenic mice overexpressing heparanase. Notably, podocytes overexpressing heparanase (H) demonstrated significantly higher survival rates and viability after exposure to Adriamycin or hydrogen peroxide, compared with mock-infected (V) podocytes. Immunofluorescence staining of kidney cryo-sections and cultured H and V podocytes as well as immunoblotting of proteins extracted from cultured cells, revealed that exposure to toxic injury resulted in a significant increase in autophagic flux in H podocytes, which was reversed by the heparanase inhibitor, Roneparstat (SST0001). Heparanase overexpression was also associated with substantial transcriptional upregulation of autophagy genes <i>BCN1, ATG5,</i> and <i>ATG12</i>, following Adriamycin treatment. Moreover, cleaved caspase-3 was attenuated in H podocytes exposed to Adriamycin, indicating lower apoptotic cell death in H vs. V podocytes. Collectively, these findings suggest that in podocytes, elevated levels of heparanase promote cytoprotection. |
| first_indexed | 2024-03-09T20:05:13Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T20:05:13Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d471da744f4c4fd49fe953ac87ef8e8f2023-11-24T00:35:24ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-10-0123201269110.3390/ijms232012691Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced InjuryHanan Abu-Tayeh Suleiman0Shereen Said1Haya Ali Saleh2Aviva Gamliel-Lazarovich3Eyas Haddad4Irina Minkov5Yaniv Zohar6Neta Ilan7Israel Vlodavsky8Zaid Abassi9Suheir Assady10Department of Nephrology and Hypertension, Rambam Health Care Campus, Haifa 3109601, IsraelRappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3109601, IsraelRappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3109601, IsraelDepartment of Nephrology and Hypertension, Rambam Health Care Campus, Haifa 3109601, IsraelRappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3109601, IsraelDepartment of Pathology, Rambam Health Care Campus, Haifa 3109601, IsraelRappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3109601, IsraelCancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 3109601, IsraelCancer and Vascular Biology Research Center, Rappaport Faculty of Medicine, Technion, Haifa 3109601, IsraelRappaport Faculty of Medicine, Technion—Israel Institute of Technology, Haifa 3109601, IsraelDepartment of Nephrology and Hypertension, Rambam Health Care Campus, Haifa 3109601, IsraelThe kidney glomerular filtration barrier (GFB) is enriched with heparan sulfate (HS) proteoglycans, which contribute to its permselectivity. The endoglycosidase heparanase cleaves HS and hence appears to be involved in the pathogenesis of kidney injury and glomerulonephritis. We have recently reported, nonetheless, that heparanase overexpression preserved glomerular structure and kidney function in an experimental model of Adriamycin-induced nephropathy. To elucidate mechanisms underlying heparanase function in podocytes—key GFB cells, we utilized a human podocyte cell line and transgenic mice overexpressing heparanase. Notably, podocytes overexpressing heparanase (H) demonstrated significantly higher survival rates and viability after exposure to Adriamycin or hydrogen peroxide, compared with mock-infected (V) podocytes. Immunofluorescence staining of kidney cryo-sections and cultured H and V podocytes as well as immunoblotting of proteins extracted from cultured cells, revealed that exposure to toxic injury resulted in a significant increase in autophagic flux in H podocytes, which was reversed by the heparanase inhibitor, Roneparstat (SST0001). Heparanase overexpression was also associated with substantial transcriptional upregulation of autophagy genes <i>BCN1, ATG5,</i> and <i>ATG12</i>, following Adriamycin treatment. Moreover, cleaved caspase-3 was attenuated in H podocytes exposed to Adriamycin, indicating lower apoptotic cell death in H vs. V podocytes. Collectively, these findings suggest that in podocytes, elevated levels of heparanase promote cytoprotection.https://www.mdpi.com/1422-0067/23/20/12691heparanaseAdriamycin nephropathyautophagypodocytescell viabilityglomerular filtration barrier |
| spellingShingle | Hanan Abu-Tayeh Suleiman Shereen Said Haya Ali Saleh Aviva Gamliel-Lazarovich Eyas Haddad Irina Minkov Yaniv Zohar Neta Ilan Israel Vlodavsky Zaid Abassi Suheir Assady Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury International Journal of Molecular Sciences heparanase Adriamycin nephropathy autophagy podocytes cell viability glomerular filtration barrier |
| title | Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury |
| title_full | Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury |
| title_fullStr | Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury |
| title_full_unstemmed | Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury |
| title_short | Heparanase Increases Podocyte Survival and Autophagic Flux after Adriamycin-Induced Injury |
| title_sort | heparanase increases podocyte survival and autophagic flux after adriamycin induced injury |
| topic | heparanase Adriamycin nephropathy autophagy podocytes cell viability glomerular filtration barrier |
| url | https://www.mdpi.com/1422-0067/23/20/12691 |
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