ArticleAging cell2022
Loss of legumain induces premature senescence and mediates aging-related renal fibrosis.
Article in Aging cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 28 citations in OpenAlex.
- Review
- Regulated cell death: a multidimensional regulatory network in the pathogenesis of renal fibrosis.Apoptosis : an international journal on programmed cell death · 2026Review
- Macrophage-derived legumain ameliorates excessive mechanical stress-induced ferroptosis of nucleus pulposus cells and intervertebral disc degeneration via integrin αvβ3-Hippo signaling.Cellular & molecular biology letters · 2026Article
- Monocyte-Derived LGMNResearch (Washington, D.C.) · 2026Article
- Inhibition of AMPKα Pathway by Podocyte GOLM1 Exacerbates Diabetic Nephrology in Mice.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Protective Effects of a ProbioticFoods (Basel, Switzerland) · 2025Article
- Cystatin 6 (CST6) and Legumain (LGMN) are potential mediators in the pathogenesis of preeclampsia.Scientific reports · 2025Article
- TXNIP deficiency attenuates renal fibrosis by modulating mTORC1/TFEB-mediated autophagy in diabetic kidney disease.Renal failure · 2024Article
- Lysosomal-Associated Protein Transmembrane 5, Tubular Senescence, and Progression of CKD.Journal of the American Society of Nephrology : JASN · 2024Article
- Mitophagy Regulates Kidney Diseases.Kidney diseases (Basel, Switzerland) · 2024Review
- Kidney Aging and Chronic Kidney Disease.International journal of molecular sciences · 2024Review
- Cathepsin X deficiency alters the processing and localisation of cathepsin L and impairs cleavage of a nuclear cathepsin L substrate.Biological chemistry · 2024Article
- Mitophagy in renal interstitial fibrosis.International urology and nephrology · 2024Review
- Aging, senescence, and cutaneous wound healing-a complex relationship.Frontiers in immunology · 2024Review
- Article
- Cellular senescence and kidney aging.Clinical science (London, England : 1979) · 2023Review
- Cellular senescence triggers intracellular acidification and lysosomal pH alkalinized via ATP6AP2 attenuation in breast cancer cells.Communications biology · 2023Article
- Mitochondrial homeostasis: a potential target for delaying renal aging.Frontiers in pharmacology · 2023Review
- Long-Term Effects of Severe Burns on the Kidneys: Research Advances and Potential Therapeutic Approaches.Journal of inflammation research · 2023Review
- The Mammalian Cysteine Protease Legumain in Health and Disease.International journal of molecular sciences · 2022Review
Corrections and comments
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Authors and funding
12 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aging is an independent risk factor for acute kidney injury and subsequent chronic kidney diseases, while the underlying mechanism is still elusive. Here, we found that renal tubules highly express a conserved lysosomal endopeptidase, legumain, which is significantly downregulated with the growing of age. Tubule-specific legumain-knockout mice exhibit spontaneous renal interstitial fibrosis from the 3rd month. In the tubule-specific legumain-knockout mice and the cultured legumain-knockdown HK-2 cells, legumain deficiency induces the activation of tubular senescence and thus increases the secretion of profibrotic senescence-associated cytokines, which in turn accelerates the activation of fibroblasts. Blockage of senescence mitigates the fibrotic lesion caused by legumain deficiency. Mechanistically, we found that silencing down of legumain leads to the elevated lysosome pH value, enlargement of lysosome size, and increase of lysosomal voltage dependent membrane channel proteins. Either legumain downregulation or aging alone induces the activation of nuclear transcription factors EB (TFEB) while it fails to further upregulate in the elderly legumain-knockdown tubules, accompanied with impaired mitophagy and increased mitochondrial ROS (mtROS) accumulation. Therapeutically, supplementation of exosomal legumain ameliorated fibronectin and collagen I production in an in vitro coculture system of tubular cells and fibroblasts. Altogether, our data demonstrate that loss of legumain in combined with aging dysregulates lysosomal homeostasis, although either aging or legumain deficiency alone induces lysosome adaptation via stimulating lysosomal biogenesis. Consequently, impaired mitophagy leads to mtROS accumulation and therefore activates tubular senescence and boosts the interstitial fibrosis.
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