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 1

GSK3β expression in glomeruli increases with age and is mainly localized to glomerular podocytes.

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GSK3β expression in glomeruli increases with age and is mainly localized...
(A) Post hoc analysis of the renal cortical transcriptome was conducted based on the Nephroseq data set derived from the Rodwell Aging Kidney study, with exclusion of subjects with abnormal serum creatinine levels or blood pressure, or other comorbid conditions. The mRNA expression levels of GSK3β, expressed as log2 median-centered intensity, are shown for subjects aged 45 to 60 years (n = 9) versus younger subjects (n = 7). P value is shown. (B) Gene set enrichment analysis of glomerular transcriptome derived from the Ju CKD Glom data set demonstrated that the expert-curated kidney-aging-related gene set RODWELL_AGING_KIDNEY_UP is enriched in high GSK3β expression phenotype. Normalized enrichment score (NES) and nominal P values are shown. (C) Non-neoplastic nephrectomy specimens were procured from patients of varying ages (young or Y, <30 years old; middle-aged or M, 30 to 59 years old; older subjects or O, 60 to 79 years old) as elaborated in Supplemental Figure 1. Consecutive kidney sections were subjected to immunohistochemical staining for GSK3β and p16INK4A, along with immunofluorescent staining for WT-1. Scale bars: 20 μm. (D and E) Linear regression analyses of the relative glomerular staining intensity of GSK3β and (D) that of p16INK4A or (E) the number of WT-1–positive podocytes per glomerular cross section (gcs) per subject (n = 6 subjects per group, 60 glomeruli analyzed per group with 10 per subject). IOD, integrated optical density. (F and G) Linear regression analyses show that the average relative glomerular staining intensity of GSK3β (F) positively correlated with the percentage of global glomerulosclerosis and (G) inversely correlated with estimated glomerular filtration rate (eGFR) (n = 6). Spearman’s correlation coefficient (R) and P value are shown. Panel A was analyzed with 2-tailed, unpaired Student’s t test. Panels D–G were statistically analyzed by linear regression.