Synaptopodin Limits TRPC6 Podocyte Surface Expression and Attenuates Proteinuria
| Autor: | Beata Tryniszewska, James O. Meyer, Lixia Yue, Andreas D. Kistler, Jochen Reiser, Hao Yu, Dolly Mehta, Stuart E. Dryer, Mohd Hafeez Faridi |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
030232 urology & nephrology Podocyte TRPC6 Mice 03 medical and health sciences 0302 clinical medicine Cyclosporin a TRPC6 Cation Channel medicine Animals Actin-binding protein TRPC Cation Channels Mice Knockout Gene knockdown biology Podocytes Chemistry Cell Membrane Microfilament Proteins General Medicine Cell biology Mice Inbred C57BL Proteinuria Basic Research 030104 developmental biology medicine.anatomical_structure Nephrology Knockout mouse biology.protein Female Synaptopodin Intracellular |
| Zdroj: | Journal of the American Society of Nephrology. 27:3308-3319 |
| ISSN: | 1533-3450 1046-6673 |
| DOI: | 10.1681/asn.2015080896 |
| Popis: | Gain-of-function mutations of classic transient receptor potential channel 6 (TRPC6) were identified in familial FSGS, and increased expression of wild-type TRPC6 in glomeruli is observed in several human acquired proteinuric diseases. Synaptopodin, an actin binding protein that is important in maintaining podocyte function, is downregulated in various glomerular diseases. Here, we investigated whether synaptopodin maintains podocyte function by regulating podocyte surface expression and activity of TRPC6. We show indirect interaction and nonrandom association of synaptopodin and TRPC6 in podocytes. Knockdown of synaptopodin in cultured mouse podocytes increased the expression of TRPC6 at the plasma membrane, whereas overexpression of synaptopodin decreased it. Mechanistically, synaptopodin–dependent TRPC6 surface expression required functional actin and microtubule cytoskeletons. Overexpression of wild–type or FSGS–inducing mutant TRPC6 in synaptopodin-depleted podocytes enhanced TRPC6–mediated calcium influx and induced apoptosis. In vivo, knockdown of synaptopodin also caused increased podocyte surface expression of TRPC6. Administration of cyclosporin A, which stabilizes synaptopodin, reduced LPS-induced proteinuria significantly in wild-type mice but to a lesser extent in TRPC6 knockout mice. Furthermore, administration of cyclosporin A reversed the LPS-induced increase in podocyte surface expression of TRPC6 in wild-type mice. Our findings suggest that alteration in synaptopodin levels under disease conditions may modify intracellular TRPC6 channel localization and activity, which further contribute to podocyte dysfunction. Reducing TRPC6 surface levels may be a new approach to restoring podocyte function. |
| Databáze: | OpenAIRE |
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