Synaptopodin Is Dispensable for Normal Podocyte Homeostasis but Is Protective in the Context of Acute Podocyte Injury.
| Autor: | Ning L; Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri., Suleiman HY; Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri., Miner JH; Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri minerj@wustl.edu. |
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| Jazyk: | angličtina |
| Zdroj: | Journal of the American Society of Nephrology : JASN [J Am Soc Nephrol] 2020 Dec; Vol. 31 (12), pp. 2815-2832. Date of Electronic Publication: 2020 Sep 16. |
| DOI: | 10.1681/ASN.2020050572 |
| Abstrakt: | Background: Synaptopodin (Synpo) is an actin-associated protein in podocytes and dendritic spines. Many functions in regulating the actin cytoskeleton via RhoA and other pathways have been ascribed to Synpo, yet no pathogenic mutations in the SYNPO gene have been discovered in patients. Naturally occurring Synpo isoforms are known (Synpo-short and -long), and a novel truncated version (Synpo-T) is upregulated in podocytes from Synpo mutant mice. Synpo-T maintains some Synpo functions, which may prevent a podocyte phenotype from emerging in unchallenged mutant mice. Methods: Novel mouse models were generated to further investigate the functions of Synpo. In one, CRISPR/Cas9 deleted most of the Synpo gene, preventing production of any detectable Synpo protein. Two other mutant strains made truncated versions of the protein. Adriamycin injections were used to challenge the mice, and Synpo functions were investigated in primary cultured podocytes. Results: Mice that could not make detectable Synpo ( Synpo -/- ) did not develop any kidney abnormalities up to 12 months of age. However, Synpo -/- mice were more susceptible to Adriamycin nephropathy. In cultured primary podocytes from mutant mice, the absence of Synpo caused loss of stress fibers, increased the number and size of focal adhesions, and impaired cell migration. Furthermore, loss of Synpo led to decreased RhoA activity and increased Rac1 activation. Conclusions: In contrast to previous findings, podocytes can function normally in vivo in the absence of any Synpo isoform. Synpo plays a protective role in the context of podocyte injury through its involvement in actin reorganization and focal adhesion dynamics. (Copyright © 2020 by the American Society of Nephrology.) |
| Databáze: | MEDLINE |
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