KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression
Despite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte loss remain poorly understood, and cell-specific therapy is lacking. We previously reported that kidney and brain expressed protein (KIBRA), encoded by WWC1, promotes podocyte injury in vitr...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2023-04-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.165002 |
| _version_ | 1797634287699230720 |
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| author | Kristin Meliambro Yanfeng Yang Marina de Cos Estefania Rodriguez Ballestas Caroline Malkin Jonathan Haydak John R. Lee Fadi Salem Laura H. Mariani Ronald E. Gordon John M. Basgen Huei Hsun Wen Jia Fu Evren U. Azeloglu John Cijiang He Jenny S. Wong Kirk N. Campbell |
| author_facet | Kristin Meliambro Yanfeng Yang Marina de Cos Estefania Rodriguez Ballestas Caroline Malkin Jonathan Haydak John R. Lee Fadi Salem Laura H. Mariani Ronald E. Gordon John M. Basgen Huei Hsun Wen Jia Fu Evren U. Azeloglu John Cijiang He Jenny S. Wong Kirk N. Campbell |
| author_sort | Kristin Meliambro |
| collection | DOAJ |
| description | Despite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte loss remain poorly understood, and cell-specific therapy is lacking. We previously reported that kidney and brain expressed protein (KIBRA), encoded by WWC1, promotes podocyte injury in vitro through activation of the Hippo signaling pathway. KIBRA expression is increased in the glomeruli of patients with focal segmental glomerulosclerosis, and KIBRA depletion in vivo is protective against acute podocyte injury. Here, we tested the consequences of transgenic podocyte-specific WWC1 expression in immortalized human podocytes and in mice, and we explored the association between glomerular WWC1 expression and glomerular disease progression. We found that KIBRA overexpression in immortalized human podocytes promoted cytoplasmic localization of Yes-associated protein (YAP), induced actin cytoskeletal reorganization, and altered focal adhesion expression and morphology. WWC1-transgenic (KIBRA-overexpressing) mice were more susceptible to acute and chronic glomerular injury, with evidence of YAP inhibition in vivo. Of clinical relevance, glomerular WWC1 expression negatively correlated with renal survival among patients with primary glomerular diseases. These findings highlight the importance of KIBRA/YAP signaling to the regulation of podocyte structural integrity and identify KIBRA-mediated injury as a potential target for podocyte-specific therapy in glomerular disease. |
| first_indexed | 2024-03-11T12:06:29Z |
| format | Article |
| id | doaj.art-427bdc10103645eb8f284f1c9af46d1b |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:06:29Z |
| publishDate | 2023-04-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-427bdc10103645eb8f284f1c9af46d1b2023-11-07T16:25:25ZengAmerican Society for Clinical investigationJCI Insight2379-37082023-04-0187KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progressionKristin MeliambroYanfeng YangMarina de CosEstefania Rodriguez BallestasCaroline MalkinJonathan HaydakJohn R. LeeFadi SalemLaura H. MarianiRonald E. GordonJohn M. BasgenHuei Hsun WenJia FuEvren U. AzelogluJohn Cijiang HeJenny S. WongKirk N. CampbellDespite recent progress in the identification of mediators of podocyte injury, mechanisms underlying podocyte loss remain poorly understood, and cell-specific therapy is lacking. We previously reported that kidney and brain expressed protein (KIBRA), encoded by WWC1, promotes podocyte injury in vitro through activation of the Hippo signaling pathway. KIBRA expression is increased in the glomeruli of patients with focal segmental glomerulosclerosis, and KIBRA depletion in vivo is protective against acute podocyte injury. Here, we tested the consequences of transgenic podocyte-specific WWC1 expression in immortalized human podocytes and in mice, and we explored the association between glomerular WWC1 expression and glomerular disease progression. We found that KIBRA overexpression in immortalized human podocytes promoted cytoplasmic localization of Yes-associated protein (YAP), induced actin cytoskeletal reorganization, and altered focal adhesion expression and morphology. WWC1-transgenic (KIBRA-overexpressing) mice were more susceptible to acute and chronic glomerular injury, with evidence of YAP inhibition in vivo. Of clinical relevance, glomerular WWC1 expression negatively correlated with renal survival among patients with primary glomerular diseases. These findings highlight the importance of KIBRA/YAP signaling to the regulation of podocyte structural integrity and identify KIBRA-mediated injury as a potential target for podocyte-specific therapy in glomerular disease.https://doi.org/10.1172/jci.insight.165002Cell biologyNephrology |
| spellingShingle | Kristin Meliambro Yanfeng Yang Marina de Cos Estefania Rodriguez Ballestas Caroline Malkin Jonathan Haydak John R. Lee Fadi Salem Laura H. Mariani Ronald E. Gordon John M. Basgen Huei Hsun Wen Jia Fu Evren U. Azeloglu John Cijiang He Jenny S. Wong Kirk N. Campbell KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression JCI Insight Cell biology Nephrology |
| title | KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression |
| title_full | KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression |
| title_fullStr | KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression |
| title_full_unstemmed | KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression |
| title_short | KIBRA upregulation increases susceptibility to podocyte injury and glomerular disease progression |
| title_sort | kibra upregulation increases susceptibility to podocyte injury and glomerular disease progression |
| topic | Cell biology Nephrology |
| url | https://doi.org/10.1172/jci.insight.165002 |
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