期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 115, 期 5, 页码 1188-1198出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200523371
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资金
- NIDA NIH HHS [DA18886, R01 DA018886] Funding Source: Medline
- NIDDK NIH HHS [R01 DK062472, DK062472, DK064236, R01 DK057683, DK57683, P50 DK064236] Funding Source: Medline
Synaptopodin is the founding member of a novel class of proline-rich actin-associated proteins highly expressed in telencephalic dendrites and renal podocytes. Synaptopodin-deficient (synpo(-/-)) mice lack the dendritic spine apparatus and display impaired activity-dependent long-term synaptic plasticity. In contrast, the ultrastructure of podocytes in synpo(-/-) mice is normal. Here we show that synpo(-/-) mice display impaired recovery from protamine sulfate-induced podocyte foot process (FP) effacement and LPS-induced nephrotic syndrome. Similarly, synpo(-/-) podocytes show impaired actin filament reformation in vitro. We further demonstrate that synaptopodin exists in 3 isoforms, neuronal Synpo-short (685 AA), renal Synpo-long (903 AA), and Synpo-T (181 AA). The C terminus of Synpo-long is identical to that of Synpo-T. All 3 isoforms specifically interact with a-actinin and elongate alpha-actinin-induced actin filaments. synpo(-/-) mice lack Synpo-short and Synpo-long expression but show an upregulation of Synpo-T protein expression in podocytes, though not in the brain. Gene silencing of Synpo-T abrogates stress-fiber formation in synpo(-/-) podocytes, demonstrating that Synpo-T serves as a backup for Synpo-long in synpo(-/-) podocytes. In concert, synaptopodin regulates the actin-bundling activity of a-actinin in highly dynamic cell compartments, such as podocyte FPs and the dendritic spine apparatus.
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