ArticleNature communications2022
Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 71 citations in OpenAlex.
- Article
- Article
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- Epigenetic dynamics of cellular senescence: From mechanistic insights to precision senotherapy.Chinese medical journal · 2026Review
- Undernutrition-related diabetes in mice is linked to early undernutrition.American journal of physiology. Endocrinology and metabolism · 2026Article
- AARS1 promotes diabetic kidney disease through rewiring Akt and NF-κB signaling to suppress autophagy and sustain inflammation.Cellular & molecular biology letters · 2026Article
- Molecular mechanisms and therapeutic strategies of glomerular cell senescence in diabetic kidney disease: from heterogeneity to precision intervention.Cellular and molecular life sciences : CMLS · 2026Review
- Abnormal lipid metabolism in senescent renal tubular cells in diabetic nephropathy.Cellular and molecular life sciences : CMLS · 2026Review
- DNMT inhibitor ameliorates hyperglycemia and renal inflammation partially via reversing hypermethylation-induced Klotho suppression in diabetic mice.Clinical epigenetics · 2026Article
- Exploring the Senotherapeutic Potential of Polyphenols in Aging and Disease: A Literature Review.International journal of molecular sciences · 2026Review
- Targeting PAR1 biased signaling with parmodulin reduces thromboinflammation and acute lung injury in sickle cell disease.Blood advances · 2026Article
- Alterations in mitochondria and cellular senescence in aged sEH null female kidneys.GeroScience · 2026Article
- Mechanistic insights into SOCS5-related DNA damage and cellular senescence in diabetic retinopathy.Cell death discovery · 2026Article
- Integrative Approaches to Treating Cellular Senescence in Kidney Disease.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Tadehagi triquetrum aqueous extract ameliorates diabetic kidney disease through mitigating epithelial senescence via the PTEN/AKT/mTOR signaling pathway.Chinese medicine · 2026Article
- Histone methyltransferase EZH2 drives podocyte injury and senescence in diabetic nephropathy through STAT3 activation.Cellular and molecular life sciences : CMLS · 2026Article
- Formononetin inhibits p53 signaling pathway activation to delay cellular senescence and ameliorates diabetic kidney disease.World journal of diabetes · 2026Article
- Dedifferentiated proximal tubular epithelial cells in diabetic kidney disease: pathogenic roles, repair potential, and therapeutic implications.Frontiers in endocrinology · 2026Review
- New Insights into the Role of Mitochondrial Dysfunction in Diabetic Kidney Disease in the Omics Era.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Review
- Review
Corrections and comments
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Authors and funding
25 authors at 9 institutions in 4 countries.
Funding
Abstract
A major obstacle in diabetes is the metabolic or hyperglycemic memory, which lacks specific therapies. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, human samples and in vitro models. Tubular and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans. Mechanistically, sustained tubular p21 expression in DKD is linked to demethylation of its promoter and reduced DNMT1 expression. Two disease resolving agents, protease activated protein C (3K3A-aPC) and parmodulin-2, reversed sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence is a pathway contributing to the hyperglycemic memory, which can be therapeutically targeted.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.