Age-related GSK3β overexpression drives podocyte senescence and glomerular aging
Yudong Fang, … , Lance D. Dworkin, Rujun Gong
Yudong Fang, … , Lance D. Dworkin, Rujun Gong
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e141848. https://doi.org/10.1172/JCI141848.
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Research Article Aging Nephrology

Age-related GSK3β overexpression drives podocyte senescence and glomerular aging

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.

Authors

Yudong Fang, Bohan Chen, Zhangsuo Liu, Athena Y. Gong, William T. Gunning, Yan Ge, Deepak Malhotra, Amira F. Gohara, Lance D. Dworkin, Rujun Gong

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Figure 8

Long-term lithium carbonate therapy in psychiatric patients inhibits GSK3β activity and attenuates cellular senescence in urinary exfoliated cells.

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Long-term lithium carbonate therapy in psychiatric patients inhibits GSK...
(A) Schematic diagram depicts preparation of urinary exfoliated cells from psychiatric patients treated either with lithium carbonate [Li (+), n = 12] or without lithium carbonate [Li (–), n = 12]. Scale bars: 100 μm. (B) Immunofluorescent staining of urinary exfoliated cells for synaptopodin (red) with DAPI counterstaining for nuclei, as shown by fluorescence microscopy and differential interference contrast (DIC) microscopy. Arrowheads indicate synaptopodin-positive podocytes, while arrows indicate synaptopodin-negative urinary cells. Scale bars: 20 μm. (C) Multicolor immunofluorescent staining of urinary exfoliated cells for phosphorylated GSK3β at serine 9 (p-GSK3βS9), p16INK4A, and WT-1. Arrows indicate WT-1–positive urinary podocytes with p-GSK3βS9-lop16hi staining pattern. Arrowheads indicate WT-1–positive urinary podocytes with p-GSK3βS9-hip16lo staining pattern. Scale bars: 100 μm. (D) Quantification of cells with high and low expression of p16INK4A among all WT-1+ urinary cells. **P < 0.01 (n = 12). (E) Immunofluorescent staining of urinary exfoliated cells for synaptopodin (SYNPO) followed by counterstaining with DAPI. Scale bars: 20 μm. (F) Immunofluorescent staining of urine exfoliated cells for γH2AX followed by counterstaining with DAPI. Scale bars: 20 μm. Absolute count of the number of γH2AX-positive cells as percentage of the number of urinary exfoliated cells per microscopic field. **P < 0.01 (n = 12). Data are expressed as mean ± SD. Panels D and F were analyzed by 2-tailed, unpaired Student’s t test.