The Klotho proteins in health and disease

Nature Reviews Nephrology, Journal Year: 2018, Volume and Issue: 15(1), P. 27 - 44

Published: Nov. 19, 2018

Language: Английский

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Food as medicine: targeting the uraemic phenotype in chronic kidney disease

Nature Reviews Nephrology, Journal Year: 2020, Volume and Issue: 17(3), P. 153 - 171

Published: Sept. 22, 2020

Language: Английский

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Inflammation and Premature Ageing in Chronic Kidney Disease

Toxins, Journal Year: 2020, Volume and Issue: 12(4), P. 227 - 227

Published: April 4, 2020

Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype contribute to impaired health status, reduced quality life, mortality in chronic kidney disease (CKD). Because there is a huge global burden due CKD, treatment strategies targeting CKD particular interest. Several distinct features may represent potential options attenuate risk progression poor outcome CKD. The nuclear factor erythroid 2-related 2 (NRF2)–kelch-like cell-derived protein with CNC homology [ECH]-associated 1 (KEAP1) signaling pathway, endocrine phosphate-fibroblast growth factor-23–klotho axis, increased cellular senescence, mitochondrial biogenesis currently most promising candidates, different pharmaceutical compounds already under evaluation. If studies humans show beneficial effects, carefully phenotyped patients can benefit from them.

Language: Английский

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Klotho, Aging, and the Failing Kidney

Frontiers in Endocrinology, Journal Year: 2020, Volume and Issue: 11

Published: Aug. 27, 2020

Klotho has been recognised as a gene involved in the ageing process mammals for over thirty years, where it regulates phosphate homeostasis and activity of members fibroblast growth factor (FGF) family. The α -Klotho protein is receptor Fibroblast Growth Factor-23 (FGF23), regulating vitamin D metabolism. Phosphate toxicity hallmark mammalian correlates with diminution levels increasing age. As such, modulation an attractive target therapeutic intervention diseasome ageing; particular chronic kidney disease (CKD), implicated directly pathophysiology. A range senotherapeutic strategies have developed to or indirectly influence expression, varying degrees success. These include administration exogenous Klotho, synthetic natural agonists indirect approaches, via foodome gut microbiota. All these approaches significant potential mitigate loss physiological function resilience accompanying old age improve outcomes within ageing.

Language: Английский

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Ageing – Oxidative stress, PTMs and disease

Molecular Aspects of Medicine, Journal Year: 2022, Volume and Issue: 86, P. 101099 - 101099

Published: June 8, 2022

Post-translational modifications (PTMs) have been proposed as a link between the oxidative stress-inflammation-ageing trinity, thereby affecting several hallmarks of ageing. Phosphorylation, acetylation, and ubiquitination cover >90% all reported PTMs. Several main PTMs are involved in normal "healthy" ageing different age-related diseases, for instance neurodegenerative, metabolic, cardiovascular, bone well cancer chronic kidney disease. Ultimately, data from human rare progeroid syndromes, but also long-living animal species, imply that critical regulators process. Mechanistically, target epigenetic non-epigenetic pathways during In particular, histone modification has implications process can modulate lifespan. Therefore, PTM-based therapeutics appear to be attractive pharmaceutical candidates reduce burden ageing-related diseases. phosphorylation acetylation inhibitors already FDA-approved treatment other diseases offer unique potential investigate both beneficial effects possible side-effects. As an example, most well-studied senolytic compounds dasatinib quercetin, which tested Phase 1 pilot studies, act kinase inhibitors, targeting cellular senescence increasing Future studies need carefully determine best "diseasome ageing".

Language: Английский

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Chronic kidney disease: Biomarker diagnosis to therapeutic targets

Clinica Chimica Acta, Journal Year: 2019, Volume and Issue: 499, P. 54 - 63

Published: Aug. 30, 2019

Language: Английский

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Arterial “inflammaging” drives vascular calcification in children on dialysis

Kidney International, Journal Year: 2019, Volume and Issue: 95(4), P. 958 - 972

Published: March 2, 2019

Children on dialysis have a cardiovascular mortality risk equivalent to older adults in the general population, and rapidly develop medial vascular calcification, an age-associated pathology. We hypothesized that premature ageing contributes calcification children with advanced chronic kidney disease (CKD). Vessels from Stage 5 CKD without had evidence of increased oxidative DNA damage. The senescence markers p16 p21 were also vessels dialysis. Treatment vessel rings ex vivo calcifying media damage CKD, but not those healthy controls. Vascular smooth muscle cells cultured exhibited persistent damage, impaired repair, accelerated senescence. Under conditions showed osteogenic differentiation calcification. These changes correlated activation senescence-associated secretory phenotype (SASP), inflammatory characterized by secretion proinflammatory cytokines growth factors. Blockade ataxia-telangiectasia mutated (ATM)-mediated signaling reduced both inflammation Clinically, elevated circulating levels SASP factors stiffness coronary artery data imply dysregulated mineral metabolism drives "inflammaging" promoting senescence, pro-inflammatory SASP. Drugs target or eliminate senescent may potential prevent patients CKD.Graphical abstract

Language: Английский

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Early Vascular Ageing and Cellular Senescence in Chronic Kidney Disease

Computational and Structural Biotechnology Journal, Journal Year: 2019, Volume and Issue: 17, P. 721 - 729

Published: Jan. 1, 2019

Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by progressive vascular disease, systemic inflammation, muscle wasting and frailty. The predominant early (EVA) process mediated medial calcification (VC) results in marked discrepancy between chronological biological age CKD. Though the exact underlying mechanisms VC EVA are not fully elucidated, accumulating evidence indicates that cellular senescence - subsequent chronic inflammation through senescence-associated secretary phenotype (SASP) plays fundamental role its initiation progression. In this review, we discuss pathophysiological links CKD, with focus on media VC, potential anti-ageing therapeutic strategies senolytic drugs targeting

Language: Английский

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Sinapic Acid Ameliorates the Progression of Streptozotocin (STZ)-Induced Diabetic Nephropathy in Rats via NRF2/HO-1 Mediated Pathways

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: July 23, 2020

Diabetic nephropathy (DN) is a major cause of end-stage kidney failure. The present study examines the amelioration renal protection sinapic acid (SA) in streptozotocin (STZ)-induced diabetic and associated mechanisms. Rats were randomly assigned into four groups: Normal control (NC), STZ, STZ + SA 20 mg/kg bw, 40 bw. After eight weeks, fasting blood glucose (FBG), ratio weight to body (renal index), 24 h urine protein, urea nitrogen (BUN), serum creatinine (SCr), reduced glutathione peroxidase (GPx), superoxide dismutase (SOD), lipid peroxidation (LPO), inflammatory marker MPO, tumor necrosis factor α (TNFα), interleukin (IL)-6, as well profile total cholesterol (TC), triglycerides (TG), very low density lipoprotein (VLDL), (LDL), high (HDL) levels assesed. histomorphology ultrastructure kidneys also assessed. In addition, protein expression transforming growth factor-β1 (TGF-β1), nuclear erythroid 2-related 2 (Nrf2), heme oxygenase-1 (HO-1), IκBα (IkBα), anti-apoptotic BCl2 , kappa B (NF-kB), Bax examined. We found that pretreatment significantly dose-dependently upregulated Nrf2, HO-1, IKBα, Bcl-2 but downregulated NF-κB, suggesting protective mechanism due its antioxidant activity; prevents release pro-inflammatory cytokines markers (TNFα IL-6 MPO), upregulates defence enzymes, reduces peroxidation, nitric oxide, activity, which may be influenced by regulation TNF-α, IL-6, Bcl-2, NF-kB, BaX via Nrf2/HO-1 signaling pathway induced DN. Thus, our results suggest ameliorates progression STZ-induced rats NRF2/HO-1 mediated pathways. Further comprehensive studies are required better understand underlying

Language: Английский

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Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies

Frontiers in Pharmacology, Journal Year: 2020, Volume and Issue: 11

Published: Dec. 11, 2020

Age-related disorders such as chronic kidney disease (CKD) are increasingly prevalent globally and pose unprecedented challenges. In many aspects, CKD can be viewed a state of accelerated premature aging. Aging share common characteristic features with increased cellular senescence, conserved program characterized by an irreversible cell cycle arrest altered transcriptome secretome. While developmental senescence acute may positively contribute to the fine-tuning embryogenesis injury repair, when unresolved promptly, plays crucial role in fibrogenesis progression. Senescent cells elicit their fibrogenic actions primarily secreting assortment inflammatory profibrotic factors known senescence-associated secretory phenotype (SASP). Increasing evidence indicates that senescent could promising new target for therapeutic intervention senotherapy, which includes depleting cells, modulating SASP restoration inhibitors. this review, we discuss current understanding mechanism fibrosis. We also highlight potential options targeting treatment CKD.

Language: Английский

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