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Background

CKD is associated with the loss of functional nephr ons, leading to increased mechanical and metabolic stress in the remaining cells, particularly for cells constituting the filtration barrier, such as podocytes. The failure of podocytes to mount an adequate stress response can lead to further nephron loss and disease progression. However, the mechanisms that regulate this degenerative process in the kidney are unknown.

Methods

We combined in vitro, in vivo, and organ-on-chip approaches to identify the RE1-silencing transcription factor (REST), a repressor of neuronal genes during embryonic development, as a central regulator of podocyte adaptation to injury and aging.

Results

Mice with a specific deletion of REST in podocytes exhibit albuminuria, podocyte apoptosis, and glomerulosclerosis during aging, and exhibit increased vulnerability to renal injury. This phenotype is mediated, in part, by the effects of REST on the podocyte cytoskeleton that promote resistance to mechanical stressors and augment podocyte survival. Finally, REST expression is upregulated in human podocytes during aging, consistent with a conserved mechanism of stress resistance.

Conclusions

These results suggest REST protects the kidney from injury and degeneration during aging, with potentially important therapeutic implications."xsd:string
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http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/author"Aron L."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/author"Isnard P."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/author"Canaud G."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/author"Legendre C."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/author"Yankner B.A."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/author"Terzi F."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/author"Magassa S."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/author"Hoguin C."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/date"2021"xsd:gYear
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/name"J Am Soc Nephrol"xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/pages"1974-1986"xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/title"REST and Stress Resistance in the Aging Kidney."xsd:string
http://purl.uniprot.org/citations/34078664http://purl.uniprot.org/core/volume"32"xsd:string
http://purl.uniprot.org/citations/34078664http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/34078664
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