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Abstract: FR-PO952

Regulation of Podocyte Senescence by GSK3β: A Novel Senostatic Target for Delaying Glomerular Aging

Session Information

Category: Glomerular Diseases

  • 1204 Podocyte Biology


  • Fang, Yudong, University of Toledo Medical Center, Toledo, Ohio, United States
  • Dworkin, Lance D., University of Toledo Medical Center, Toledo, Ohio, United States
  • Gong, Rujun, University of Toledo Medical Center, Toledo, Ohio, United States

Along with worldwide population aging, nephrology practice is challenged by renal aging, which is associated with progression of age-related glomerulosclerosis centrally involving podocyte senescence. Compelling evidence suggests that microdoses of lithium, an inhibitor of GSK3β, alleviated aging in Drosophila and C. elegans. As a multitasking kinase, GSK3β has also lately been implicated in podocyte pathobiology. However, it remains unknown if GSK3β regulates renal aging.


Renal aging was examined in mice with doxycycline-induced podocyte-specific ablation of GSK3β (KO) or in control littermates at 2, 12 or 24 months. Cultured podocytes were tested for senescence.


Accompanying aging, control mice exhibited evident renal aging, featured by a decline in renal function, persistent albuminuria and typical pathologic changes, including glomerular hypertrophy, focal global glomerulosclerosis, hyaline arteriolosclerosis and renal fibrosis on light microscopy, associated with ultrastructural lesions in podocytes like foot process effacement and deposits of protein aggregates, podocytopenia, and loss of podocyte markers like synaptopodin and podocin. In parallel, senescence-associated β-galactosidase activity and expression of senescence-related p16INK4A, p53 and p21 were progressively increased in glomeruli, correlated with concomitant GSK3β overactivity, as evidenced by linear regression analysis. In the aged KO mice, GSK3β was selectively ablated in podocytes, resulting in a blunted induction of p16INK4A, p53, p21 and β-galactosidase activity in glomeruli, and alleviation of glomerulosclerosis and other signs of glomerular aging. Mechanistically, in silico analysis revealed that p16INK4A, p53 and p21 are cognate substrates of GSK3β and contain the GSK3β consensus motifs. In vitro, ectopic expression of a constitutively active GSK3β mutant in podocytes promoted phosphorylation of p16INK4A, p53 and p21, incurring a potentiated cellular senescence, marked by an elevated β-galactosidase activity and loss of podocyte differentiation markers like synaptopodin. Conversely, GSK3β knockdown attenuated phosphorylation of p16INK4A, p53 and p21, leading to a diminished cellular senescence.


GSK3β plays a key role in glomerular aging by regulating podocyte senescence, and thus is likely an actionable senostatic target for delaying glomerular aging.