The fibrogenic niche in kidney fibrosis: components and mechanisms

Nature Reviews Nephrology, Год журнала: 2022, Номер 18(9), С. 545 - 557

Опубликована: Июль 4, 2022

Язык: Английский

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Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1β-dependent macrophage activation and tubular cell senescence

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Апрель 13, 2024

Abstract Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells abnormally elevated fibrotic kidneys. By screening these crotonylated/acetylated factors, crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) found to remarkably increase 3 9 (H3K9cr) level without influencing H3K9ac kidneys and cells. The integrated analysis ChIP-seq RNA-seq reveal the hub proinflammatory cytokine IL-1β, which regulated by H3K9cr, play crucial fibrogenesis. Furthermore, genetic pharmacologic inhibition both suppress H3K9cr-mediated IL-1β expression, thereby alleviate IL-1β-dependent macrophage activation cell senescence delay renal Collectively, our findings uncover H3K9cr exerts critical, previously unrecognized role fibrosis, where represents an attractive drug target slow disease progression.

Язык: Английский

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Fibroageing: An ageing pathological feature driven by dysregulated extracellular matrix-cell mechanobiology

Ageing Research Reviews, Год журнала: 2021, Номер 70, С. 101393 - 101393

Опубликована: Июнь 15, 2021

Ageing is a multifactorial biological process leading to progressive decline of physiological functions. The ageing includes numerous changes in the cells and interactions between cell-cell cell-microenvironment remaining as critical risk factor for development chronic degenerative diseases. Systemic inflammation, known inflammageing, increases consequence contributing age-related morbidities. But also, persistent uncontrolled activation fibrotic pathways, with excessive accumulation extracellular matrix (ECM) organ dysfunction markedly more frequent elderly. In this context, we introduce here concept Fibroageing, that is, propensity develop tissue fibrosis associated ageing, propose ECM key player underlying process. During molecules become damaged through many modifications including glycation, crosslinking, accumulation, stiffness which intensifies ageing-associated alterations. We provide framework some mechanistic hypotheses proposing stiff ECM, addition well-known positive feedback loops, affect several hallmarks such cell senescence mitochondrial dysfunction, mechanism driver thread Fibroageing.

Язык: Английский

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β‐catenin‐controlled tubular cell‐derived exosomes play a key role in fibroblast activation via the OPN‐CD44 axis

Journal of Extracellular Vesicles, Год журнала: 2022, Номер 11(3)

Опубликована: Март 1, 2022

Abstract Tubular injury and peripheral fibroblast activation are the hallmarks of chronic kidney disease (CKD), suggesting intimate communication between two types cells. However, underlying mechanisms remain to be determined. Exosomes play a role in shuttling proteins other materials recipient In our study, we found that exosomes were aroused by β‐catenin renal tubular Osteopontin (OPN), especially its N‐terminal fragment (N‐OPN), was encapsulated β‐catenin‐controlled cell‐derived exosome cargo, subsequently passed fibroblasts. Through binding with CD44, exosomal OPN promoted proliferation activation. Gene deletion cells (Ksp‐β‐catenin −/− ) or gene ablation CD44 (CD44 greatly ameliorated fibrosis. Notably, N‐OPN carried secreted into urine patients CKD, negatively correlated function. The urinary from CKD accelerated fibrosis, which blocked deletion. These results suggest exosome‐mediated OPN/CD44 axis plays key is controlled β‐catenin.

Язык: Английский

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Autophagy and Renal Fibrosis

Aging and Disease, Год журнала: 2022, Номер 13(3), С. 712 - 712

Опубликована: Янв. 1, 2022

Renal fibrosis is a common process of almost all the chronic kidney diseases progressing to end-stage disease. As highly conserved lysosomal protein degradation pathway, autophagy responsible for degrading aggregates, damaged organelles, or invading pathogens maintain intracellular homeostasis. Growing evidence reveals that involved in progression renal fibrosis, both tubulointerstitial compartment and glomeruli. Nevertheless, specific role has still not been fully understood. Therefore, this review we will describe characteristics summarize recent advances understanding functions fibrosis. Moreover, problem existing field possibility as potential therapeutic target have also discussed.

Язык: Английский

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Molecular Mechanisms of Kidney Injury and Repair

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(3), С. 1542 - 1542

Опубликована: Янв. 28, 2022

Chronic kidney disease (CKD) will become the fifth global cause of death by 2040, thus emphasizing need to better understand molecular mechanisms damage and regeneration in kidney. CKD predisposes acute injury (AKI) which, turn, promotes progression. This implies that or AKI-to-CKD transition are associated with dysfunctional repair mechanisms. Current therapeutic options slow progression but fail treat accelerate recovery from AKI unable promote regeneration. Unraveling cellular involved repair, including failure this process, may provide novel biomarkers tools. We now review contribution different events transition, focusing on role macrophages injury, forms regulated cell necroinflammation, senescence senescence-associated secretory phenotype (SAPS), polyploidization, podocyte activation parietal epithelial cells. Next, we discuss key contributors opportunities for their manipulation, a focus resident renal progenitor cells, stem cells reparative secretome, certain macrophage subphenotypes within M2 senescent clearance.

Язык: Английский

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Cellular senescence of renal tubular epithelial cells in renal fibrosis

Frontiers in Endocrinology, Год журнала: 2023, Номер 14

Опубликована: Фев. 28, 2023

Renal fibrosis (RF) is the common pathological manifestation of virtually all chronic kidney diseases (CKD) and one major causes end-stage renal disease (ESRD), but pathogenesis which still unclear. tubulointerstitial lesions have been identified as a key hallmark RF pathology. tubular epithelial cells are resident tubulointerstitium play an important role in recovery versus following injury. Studies recent years shown that senescence can accelerate progression fibrosis. Oxidative stress(OS), telomere attrition DNA damage cell senescence. Current interventions therapeutic strategies for cellular include calorie restriction routine exercise, Klotho, senolytics, senostatics, other related drugs. This paper provides overview mechanisms signaling pathways including Wnt/β-catenin/RAS, Nrf2/ARE STAT-3/NF-κB pathway involved therapies targeting future potential patients. These findings may offer promise further treatment CKD.

Язык: Английский

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Long-term dasatinib plus quercetin effects on aging outcomes and inflammation in nonhuman primates: implications for senolytic clinical trial design

GeroScience, Год журнала: 2023, Номер 45(5), С. 2785 - 2803

Опубликована: Июнь 1, 2023

Язык: Английский

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Tubular injury in diabetic kidney disease: molecular mechanisms and potential therapeutic perspectives

Frontiers in Endocrinology, Год журнала: 2023, Номер 14

Опубликована: Авг. 2, 2023

Diabetic kidney disease (DKD) is a chronic complication of diabetes and the leading cause end-stage renal (ESRD) worldwide. Currently, there are limited therapeutic drugs available for DKD. While previous research has primarily focused on glomerular injury, recent studies have increasingly emphasized role tubular injury in pathogenesis Various factors, including hyperglycemia, lipid accumulation, oxidative stress, hypoxia, RAAS, ER inflammation, EMT programmed cell death, been shown to induce contribute progression Additionally, traditional hypoglycemic drugs, anti-inflammation therapies, anti-senescence mineralocorticoid receptor antagonists, stem therapies demonstrated their potential alleviate This review will provide insights into latest mechanisms treatments

Язык: Английский

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Post-translational modifications in kidney diseases and associated cardiovascular risk

Nature Reviews Nephrology, Год журнала: 2024, Номер 20(8), С. 495 - 512

Опубликована: Апрель 25, 2024

Язык: Английский

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