The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family activation

Kidney International, Год журнала: 2024, Номер 106(2), С. 226 - 240

Опубликована: Май 22, 2024

Persistently elevated glycolysis in kidney has been demonstrated to promote chronic disease (CKD). However, the underlying mechanism remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced proximal tubular cells (PTCs) following ischemia-reperfusion injury (IRI) mice, as well multiple etiologies of patients with CKD. PFKFB3 expression positively correlated severity fibrosis. Moreover, CKD and mice exhibited increased urinary lactate/creatine levels lactate, respectively. PTC-specific deletion significantly reduced lactate levels, mitigated inflammation fibrosis, preserved function IRI mouse model. Similar protective effects were heterozygous deficiency or those treated inhibitor. Mechanistically, derived from PFKFB3-mediated reprogramming markedly enhanced histone lactylation, particularly H4K12la, which enriched at promoter NF-κB signaling genes like Ikbkb, Rela, Relb, activating their transcription facilitating inflammatory response. Further, inhibited activation IKKβ, I κ B α, p65 kidneys. H4K12la fibrosis These findings suggest may play dual role enhancing by promoting both H4K12la-mediated gene its activation. Thus, targeting pathway could be novel strategy for therapy.

Язык: Английский

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Biological effects and mechanisms of fisetin in cancer: a promising anti-cancer agent

European journal of medical research, Год журнала: 2023, Номер 28(1)

Опубликована: Авг. 25, 2023

Abstract Fisetin, a natural flavonoid, possesses numerous biological activities that have been extensively studied in various diseases. When it comes to cancer, fisetin exhibits range of effects, such as suppressing cell growth, triggering programmed death, reducing the formation new blood vessels, protecting against oxidative stress, and inhibiting migration. Moreover, has ability enhance effectiveness chemotherapy. The anticancer properties can be attributed diverse array molecules signaling pathways, including vascular endothelial growth factor (VEGF), mitogen-activated protein kinase (MAPK), nuclear factor-kappa B (NF-κB), PI3K/Akt/mTOR, Nrf2/HO-1. Consequently, holds promise therapeutic agent for treatment. In this review, we place emphasis on functions molecular targets therapy.

Язык: Английский

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Rodent models of AKI and AKI-CKD transition: an update in 2024

AJP Renal Physiology, Год журнала: 2024, Номер 326(4), С. F563 - F583

Опубликована: Фев. 1, 2024

Despite known drawbacks, rodent models are essential tools in the research of renal development, physiology, and pathogenesis. In past decade, have been developed used to mimic different etiologies acute kidney injury (AKI), AKI chronic disease (CKD) transition or progression, with comorbidities. These applied for both mechanistic preclinical drug development. However, current their limitations, especially since they often do not fully recapitulate pathophysiology human patients, thus need further refinement. Here, we discuss present status these models, including pathophysiologic compatibility, clinical translational significance, key factors affecting model consistency, main limitations. Future efforts should focus on establishing robust that simulate major molecular phenotypes its progression.

Язык: Английский

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Targeting Cellular Senescence in Aging and Age-Related Diseases: Challenges, Considerations, and the Emerging Role of Senolytic and Senomorphic Therapies

Aging and Disease, Год журнала: 2024, Номер unknown

Опубликована: Янв. 1, 2024

Cellular senescence is characterized by the permanent arrest of cell proliferation and a response to endogenous exogenous stress. The continuous accumulation senescent cells (SnCs) in body leads development aging age-related diseases (such as neurodegenerative diseases, cancer, metabolic cardiovascular osteoarthritis). In face growing challenge several compounds have received widespread attention for their potential target SnCs. As result, senolytics (compounds that selectively eliminate SnCs) senomorphics alter intercellular communication modulate behavior become hot research topics field anti-aging. addition, strategies such combination therapies immune-based approaches also made significant progress anti-aging therapy. this article, we discuss latest on targeting SnCs gain deeper understanding mechanism action impact different with aim providing more effective references therapeutic ideas clinical treatment ever-grave challenges diseases.

Язык: Английский

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Activation of senescence in critically ill patients: mechanisms, consequences and therapeutic opportunities

Annals of Intensive Care, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 5, 2024

Abstract Whereas aging is a whole-organism process, senescence cell mechanism that can be triggered by several stimuli. There increasing evidence critical conditions activate programs irrespective of patient’s age. In this review, we briefly describe the basic pathways and consequences their activation in critically ill patients. The available suggests paradigm which beneficial short term rendering cells resistant to apoptosis, but also detrimental late phase inducing pro-inflammatory pro-fibrotic state. Senescence therapeutic target. use drugs eliminate senescent (senolytics) or senescence-associated phenotype (senomorphics) will require monitoring these responses identification windows improve outcome

Язык: Английский

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Cellular senescence and kidney aging

Clinical Science, Год журнала: 2023, Номер 137(24), С. 1805 - 1821

Опубликована: Дек. 1, 2023

Abstract Life expectancy is increasing worldwide, and by 2050 the proportion of world’s population over 65 years age estimated to surpass 1.5 billion. Kidney aging associated with molecular physiological changes that cause a loss renal function regenerative potential. As grows, it crucial understand mechanisms underlying these changes, as they increase susceptibility developing acute kidney injury (AKI) chronic disease (CKD). Various cellular processes pathways take part in complex process aging. In this review, we will focus on phenomenon senescence one involved at crossroad aging, age-related disease, CKD. We highlight experimental clinical findings about role addition, review challenges research emerging therapeutic aspects. great potential senolytic strategies for elimination harmful senescent cells promote healthy avoid This aims give insight into recent discoveries future developments, providing comprehensive overview current knowledge anti-senescent therapies field.

Язык: Английский

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Autophagy activates EGR1 via MAPK/ERK to induce FGF2 in renal tubular cells for fibroblast activation and fibrosis during maladaptive kidney repair

Autophagy, Год журнала: 2023, Номер 20(5), С. 1032 - 1053

Опубликована: Ноя. 18, 2023

Macroautophagy/autophagy contributes to maladaptive kidney repair by inducing pro-fibrotic factors such as FGF2 (fibroblast growth factor 2), but the underlying mechanism remains elusive. Here, we show that EGR1 (early response 1) was induced in injured proximal tubules after ischemic acute injury (AKI) and this induction suppressed autophagy deficiency inducible, renal tubule-specific atg7 (autophagy related 7) knockout (iRT-atg7 KO) mice. In cultured tubular cells, TGFB1 (transforming beta also dependent. Egr1 knockdown cells reduced expression during treatment, leading less secretion decreased paracrine effects on fibroblasts. ChIP assay detected an increased binding of Fgf2 gene promoter TGFB1-treated cells. Both transcription inhibited neutralizing antibody, suggesting a positive feedback for EGR1-mediated autoregulation. This confirmed using fgf2-deficient Upstream EGR1, mice MAPK/ERK (mitogen-activated protein kinase) activation post-ischemic tubules. inhibition correlated with SQSTM1/p62 (sequestosome aggregation its sequestration MAPK/ERK. interacted blocked treatment autophagy-deficient Inhibition tubules, amelioration fibrosis improvement function. These results suggest activates which induces transactivate FGF2. is then secreted into interstitium stimulate fibroblasts fibrogenesis.

Язык: Английский

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Melatonin Mitigates Atrazine-Induced Renal Tubular Epithelial Cell Senescence by Promoting Parkin-Mediated Mitophagy

Research, Год журнала: 2024, Номер 7

Опубликована: Янв. 1, 2024

The accumulation of senescent cells in kidneys is considered to contribute age-related diseases and organismal aging. Mitochondria are a regulator cell senescence process. Atrazine as triazine herbicide poses threat renal health by disrupting mitochondrial homeostasis. Melatonin plays critical role maintaining present study aims explore the mechanism which melatonin alleviates atrazine-induced injury whether parkin-mediated mitophagy contributes mitigating senescence. found that level parkin was decreased after atrazine exposure negatively correlated with markers. treatment increased serum levels mitigates tubular epithelial Mechanistically, maintains integrity crista structure increasing contact site cristae organizing system, transcription factor A (TFAM), adenosine triphosphatase family AAA domain-containing protein 3A (ATAD3A), sorting assembly machinery 50 (Sam50) prevent DNA release subsequent activation cyclic guanosine 5′-monophosphate–adenosine 5′-monophosphate synthase pathway. Furthermore, activates Sirtuin 3–superoxide dismutase 2 axis eliminate reactive oxygen species kidney. More importantly, antisenescence largely determined parkin-dependent mitophagy. These results offer novel insights into measures against Parkin-mediated promising drug target for alleviating

Язык: Английский

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Effects of Fisetin Treatment on Cellular Senescence of Various Tissues and Organs of Old Sheep

Antioxidants, Год журнала: 2023, Номер 12(8), С. 1646 - 1646

Опубликована: Авг. 21, 2023

Fisetin has been shown to be beneficial for brain injury and age-related disease via different mechanisms. The purpose of this study was determine the presence senescent cells effects fisetin on cellular senescence in other vital organs old sheep, a more translational model. Female sheep 6–7 years (N = 6) were treated with 100 mg/kg or vehicle alone two consecutive days week 8 weeks. All harvested at time sacrifice. Histology, immunofluorescence staining, RT-Q-PCR performed regions tissues organs. Our results indicated that treatment current regimen did not affect general morphology brain. both cerebral cortex cerebellum non-Cornu Ammonis (CA) area hippocampus detected by senescent-associated β-galactosidase (SA-β-Gal) staining GL13 (lipofuscin) staining. mainly neurons gray white matter either cortex, cerebellum, non-CA hippocampus. Very few CA1-4 hippocampus, as revealed GLB1 colocalization NEUN. significantly decreased number SA-β-Gal+ GL13+ showed decreasing trend cerebellum. Furthermore, P16+ GLB1+ neuronal nuclear protein (NEUN)+ neurons, glial fibrillary acidic (GFAP)+ astrocytes, ionized calcium binding adaptor molecule 1 (IBA1)+ microglia cortex. cells, NEUN+ plasma S100B. At mRNA level, downregulated liver, lung, heart, spleen tissues, P21 expression liver lung. TREM2 lung downregulation spleen, heart. A significant decrease NRLP3 observed after treatment. Finally, SOD1 while upregulating CAT spleen. In conclusion, we found widely present sheep. addition, gene expressions inflammasomes organs, such liver. represents promising therapeutic strategy diseases.

Язык: Английский

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PAR2‐mediated cellular senescence promotes inflammation and fibrosis in aging and chronic kidney disease

Aging Cell, Год журнала: 2024, Номер 23(8)

Опубликована: Апрель 30, 2024

Cellular senescence contributes to inflammatory kidney disease via the secretion of and profibrotic factors. Protease-activating receptor 2 (PAR2) is a key regulator inflammation in diseases. However, relationship between PAR2 cellular has not yet been described. In this study, we found that PAR2-mediated metabolic changes renal tubular epithelial cells induced increased responses. Using an aging injury model, expression was shown be associated with senescence. Under vitro conditions NRK52E cells, activation induces cell senescent showed defective fatty acid oxidation (FAO). Cpt1α inhibition similar phenotype implicating important role FAO Finally, subjected mice lacking injury. PAR2-deficient kidneys are protected from adenine- cisplatin-induced fibrosis injury, respectively, by reducing inflammation. Moreover, exhibited reduced numbers during aging. These findings offer fresh insights into mechanisms underlying indicate targeting or may promising therapeutic approach for managing

Язык: Английский

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