Age-related GSK3β overexpression drives podocyte senescence and glomerular aging

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

doi:10.1172/jci141848

Cited by 51 publications

(36 citation statements)

References 62 publications

(130 reference statements)

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“…Therapeutic agents targeting GSK3β that could surmount chemoresistance of PCa ( Pecoraro et al, 2021 ). Similarly, suppressing GSK3β could delay kidney aging ( Fang et al, 2022 ). Expression and secretion of PLAU in senescent cells mediates cell proliferation and apoptosis ( Hildenbrand et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Construction and validation of an aging-related gene signature predicting the prognosis of pancreatic cancer

et al. 2023

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Background: Pancreatic cancer is a malignancy with a high mortality rate and worse prognosis. Recently, public databases and bioinformatics tools make it easy to develop the prognostic risk model of pancreatic cancer, but the aging-related risk signature has not been reported. The present study aimed to identify an aging-related risk signature with potential prognostic value for pancreatic cancer patients.Method: Gene expression profiling and human clinical information of pancreatic cancer were derived from The Cancer Genome Atlas database (TCGA). Aging-related gene sets were downloaded from The Molecular Signatures Database and aging-related genes were obtained from the Human Ageing Genomic Resources database. Firstly, Gene set enrichment analysis was carried out to investigate the role of aging process in pancreatic cancer. Secondly, differentially expressed genes and aging-related prognostic genes were screened on the basis of the overall survival information. Then, univariate COX and LASSO analysis were performed to establish an aging-related risk signature of pancreatic cancer patients. To facilitate clinical application, a nomogram was established to predict the survival rates of PCa patients. The correlations of risk score with clinical features and immune status were evaluated. Finally, potential therapeutic drugs were screened based on the connectivity map (Cmap) database and verified by molecular docking. For further validation, the protein levels of aging-related genes in normal and tumor tissues were detected in the Human Protein Atlas (HPA) database.Result: The genes of pancreatic cancer were markedly enriched in several aging-associated signaling pathways. We identified 14 key aging-related genes related to prognosis from 9,020 differentially expressed genes and establish an aging-related risk signature. This risk model indicated a strong prognostic capability both in the training set of TCGA cohort and the validation set of PACA-CA cohort and GSE62452 cohort. A nomogram combining risk score and clinical variables was built, and calibration curve and Decision curve analysis (DCA) have proved that it has a good predictive value. Additionally, the risk score was tightly linked with tumor immune microenvironment, immune checkpoints and proinflammatory factors. Moreover, a candidate drug, BRD-A47144777, was screened and verified by molecular docking, indicating this drug has the potential to treat PCa. The protein expression levels of GSK3B, SERPINE1, TOP2A, FEN1 and HIC1 were consistent with our predicted results.Conclusion: In conclusion, we identified an aging-related signature and nomogram with high prediction performance of survival and immune cell infiltration for pancreatic cancer. This signature might potentially help in providing personalized immunotherapy for patients with pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Construction and validation of an aging-related gene signature predicting the prognosis of pancreatic cancer

et al. 2023

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“…While a recent study demonstrated a critical role of GSK3b as a mechanism involved in podocyte aging in general ( 24 ), the causes of podocyte changes in aged kidneys are still not completely understood ( 25 ). To gain insights into candidate mechanisms at the transcriptomic level, we recently performed bulk RNA-Seq comparing podocytes from 2- to 3-month-old mice (corresponding to ~20-year-old humans) versus 24-month-old mice (corresponding to humans older than ~70 years) ( 26 ).…”

Section: Introductionmentioning

confidence: 99%

Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

Pippin¹,

Kaverina²,

Wang³

et al. 2022

Journal of Clinical Investigation

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With an aging population, kidney health becomes an important medical and socioeconomic factor. Kidney aging mechanisms are not well understood. We previously showed that podocytes isolated from aged mice exhibit increased expression of programmed cell death protein 1 (PD-1) surface receptor and its 2 ligands (PD-L1 and PD-L2). PDCD1 transcript increased with age in microdissected human glomeruli, which correlated with lower estimated glomerular filtration rate and higher segmental glomerulosclerosis and vascular arterial intima-to-lumen ratio. In vitro studies in podocytes demonstrated a critical role for PD-1 signaling in cell survival and in the induction of a senescence-associated secretory phenotype. To prove PD-1 signaling was critical to podocyte aging, aged mice were injected with anti–PD-1 antibody. Treatment significantly improved the aging phenotype in both kidney and liver. In the glomerulus, it increased the life span of podocytes, but not that of parietal epithelial, mesangial, or endothelial cells. Transcriptomic and immunohistochemistry studies demonstrated that anti–PD-1 antibody treatment improved the health span of podocytes. Administering the same anti–PD-1 antibody to young mice with experimental focal segmental glomerulosclerosis (FSGS) lowered proteinuria and improved podocyte number. These results suggest a critical contribution of increased PD-1 signaling toward both kidney and liver aging and in FSGS.

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“…While the underlying pathophysiological mechanism through which lithium potentially could reduce renal function remains unclear, it has been suggested that genetic susceptibility may confer an increased risk of lithium‐induced decline in eGFR 26 . At the same time, evidence emerges that lithium might inhibit glycogen synthase kinase‐3β, thus preventing age‐related loss of glomerular function 27 …”

Section: Discussionmentioning

confidence: 99%

“…26 At the same time, evidence emerges that lithium might inhibit glycogen synthase kinase-3β, thus preventing age-related loss of glomerular function. 27 There are several strengths with the present analysis: Firstly, we improved the outcome definition by using creatinine measurements to assess cases of incident CKD, rather than relying on hospital diagnoses, as most cases of uncomplicated early-stage CKD in Denmark are handled in primary care. To verify that individuals were in fact cases of incident CKD or eligible as controls, we required at least two measurements for each individual to confirm this status.…”

Section: Discussionmentioning

confidence: 99%

Lithium and the risk of chronic kidney disease: A population‐based case–control study

Winkel

Nybo

Hallas

et al. 2022

Basic Clin Pharma Tox

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The association between lithium use and chronic kidney disease (CKD) needs further evaluation. We aimed to investigate this association using Danish nationwide healthcare registers and routinely collected plasma creatinine measurements from the Funen Laboratory Cohort. We conducted a case-control study nested within the population of Funen, 2001-2015. Incident cases of CKD (estimated glomerular filtration rate <60 ml/min/1.73m 2 ; n = 21 432) were matched with four CKD-free controls on age, sex and calendar time (n = 85 532).We estimated odds ratios (OR) for the association between lithium exposure and CKD using conditional logistic regression models, adjusted for known risk factors for CKD. Ever-use of lithium was associated with an increased risk of CKD (adjusted OR [aOR]: 1.57; 95% confidence interval [CI]: 1.33-1.85). A stronger association was seen with current use of lithium (aOR: 1.92; 95%CI:1.58-2.33) and long-term use of lithium (>10 years: aOR: 3.02; 95%CI: 2.00-4.56). Furthermore, we found evidence of a dose-response relationship between cumulative dose of lithium and the risk of CKD. In conclusion, the use of lithium, especially long-term, is associated with an increased risk of CKD, although the extent to which detection bias and confounding by indication contribute to the association is unclear. Monitoring of kidney function in lithium users remains mandatory to identify individuals in which switching to alternative medications should be considered.case-control study, chronic kidney disease, lithium, pharmacoepidemiology, psychopharmacology | BACKGROUNDLithium has been used to treat bipolar disease since the 1950s and is considered an almost gold standard mood stabilizer with substantial evidence of efficacy as antimanic and relapse preventive treatment and some evidence of efficacy in the treatment of depressive episodes associated with bipolar disorder. [1][2][3][4] Despite documented effectiveness, the clinical use of lithium requires skilful and careful monitoring and management due to

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Age-related GSK3β overexpression drives podocyte senescence and glomerular aging

Cited by 51 publications

References 62 publications

Construction and validation of an aging-related gene signature predicting the prognosis of pancreatic cancer

Construction and validation of an aging-related gene signature predicting the prognosis of pancreatic cancer

Upregulated PD-1 signaling antagonizes glomerular health in aged kidneys and disease

Lithium and the risk of chronic kidney disease: A population‐based case–control study

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