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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.

Synaptopodin Is Dispensable for Normal Podocyte Homeostasis but Is Protective in the Context of Acute Podocyte Injury