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Cited by 92Renal Diseases and GlomerulopathiesTelomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model Organisms

Age-related GSK3β overexpression drives podocyte senescence and glomerular aging

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Fang, Yudong, Chen, Bohan, Liu, Zhangsuo, Gong, Athena Y., Gunning, William T., Ge, Yan, Malhotra, Deepak, Gohara, Amira F. +2 more·2022·Journal of Clinical Investigation
DOI 10.1172/jci141848PMC PMC8843754
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Abstract

As life expectancy continues to increase, clinicians are challenged by age-related renal impairment that involves podocyte senescence and glomerulosclerosis. There is now compelling evidence that lithium has a potent antiaging activity that ameliorates brain aging and increases longevity in Drosophila and Caenorhabditis elegans. As the major molecular target of lithium action and a multitasking protein kinase recently implicated in a variety of renal diseases, glycogen synthase kinase 3β (GSK3β) is overexpressed and hyperactive with age in glomerular podocytes, correlating with functional and histological signs of kidney aging. Moreover, podocyte-specific ablation of GSK3β substantially attenuated podocyte senescence and glomerular aging in mice. Mechanistically, key mediators of senescence signaling, such as p16INK4A and p53, contain high numbers of GSK3β consensus motifs, physically interact with GSK3β, and act as its putative substrates. In addition, therapeutic targeting of GSK3β by microdose lithium later in life reduced senescence signaling and delayed kidney aging in mice. Furthermore, in psychiatric patients, lithium carbonate therapy inhibited GSK3β activity and mitigated senescence signaling in urinary exfoliated podocytes and was associated with preservation of kidney function. Thus, GSK3β appears to play a key role in podocyte senescence by modulating senescence signaling and may be an actionable senostatic target to delay kidney aging.

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  • Senescent glomerular endothelial cells overexpress CDKN1A, TP53BP1, γH2AX and SERPINE1.

    “Senescent glomerular endothelial cells overexpress CDKN1A, the DNA damage markers TP53BP1 and γH2AX, and SERPINE1140,142,143.”

    From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [143]

    The Results section on senescence signaling in glomerular podocytes reports increased p21 (CDKN1A), uses γH2AX staining to assess senescence, and identifies PAI-1 (SERPINE1) as a senescence-associated factor. Those findings concern podocytes, not glomerular endothelial cells; γH2AX is not reported there as overexpressed, and the searched passages do not report TP53BP1 overexpression. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Fang, Y., Chen, B., Liu, Z., Gong, A. Y., Gunning, W. T., Ge, Y., Malhotra, D., Gohara, A. F., Dworkin, L. D., & Gong, R.
Affiliations
  • First Affiliated Hospital of Zhengzhou University (CN)
  • Brown University (US)
Corresponding author
Gong, Rujun
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2022-02-15
Volume
132
Issue
4
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci141848
PMC
PMC8843754
OpenAlex
W4213021225
Cited by
92
References
4
Citations by year
2026: 9 · 2025: 24 · 2024: 26 · 2023: 20 · 2022: 12 · 2020: 1
FWCI
13.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Investigation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
the U.S. National Institutes of Health (R01DK114006)
Topics
  • Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
GSK3β, kidney aging, lithium, glomerulosclerosis, p16INK4a, p53
MeSH terms
Glycogen Synthase Kinase 3 beta, Adult, Aging, Animals, Female, Humans, Male, Middle Aged, Gene Expression Regulation, Enzymologic, Cellular Senescence, Mice, Knockout, Podocytes, Mice

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