Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging

Cells, Год журнала: 2024, Номер 13(17), С. 1413 - 1413

Опубликована: Авг. 24, 2024

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia anomalies. Importantly, it associated with chronic pathologies (often age-related) that have inflammatory component. This includes atherosclerosis, diabetes Alzheimer's disease. Its mode of action these diseases not well understood, but inhibits or regulates multiple major pathways. has a membrane form soluble (s-Klotho). Cytosolic postulated characterized. s-Klotho endocrine properties are incompletely elucidated. binds to FGF receptor 1c (FGFR1c) widely expressed (including endothelial cells). also attaches FGF23, FGF23/Klotho FGFRs. Thus, might be roaming FGF23 coreceptor, functions. Notably, (cell-bound soluble) counteracts inflammation appears mitigate related aging (inflammaging). NF-κB NLRP3 inflammasome. inflammasome requires priming by produces active IL-1β, pores cell death (pyroptosis). In accord, countered injury induced toxins, damage-associated molecular patterns (DAMPs), cytokines, reactive oxygen species (ROS). blocks TGF-β Wnt ligands, which lessens fibrotic Low loss muscle mass (sarcopenia), as occurs diseases. counters inhibitory effects myostatin on muscle, reduces inflammation, improves repair following injury. inhibition factors may protective diabetic retinopathy age-related macular degeneration (AMD). review examines functions especially potential applications.

Язык: Английский

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Klotho antiaging protein: molecular mechanisms and therapeutic potential in diseases

Molecular Biomedicine, Год журнала: 2025, Номер 6(1)

Опубликована: Март 22, 2025

Abstract Klotho, initially introduced as an anti-aging protein, is expressed in the brain, pancreas, and most prominently kidney. The two forms of Klotho (membrane-bound soluble form) have diverse pharmacological functions such anti-inflammatory, anti-oxidative, anti-fibrotic, tumour-suppressive etc. membrane-bound form plays a pivotal role maintaining kidney homeostasis by regulating fibroblast growth factor 23 (FGF 23) signalling, vitamin D metabolism phosphate balance. deficiency has been linked with significantly reduced protection against various pathological phenotypes, including diabetic disease (DKD), which major cause chronic leading to end-stage disease. Owing pleiotropic actions klotho, it shown beneficial effects DKD tackling complex pathophysiology reducing inflammation, oxidative stress, well fibrosis. Moreover, protective effect klotho extends beyond other conditions, cardiovascular diseases, alzheimer's disease, cancer, inflammatory bowel liver Therefore, this review summarizes relationship between expression diseases special emphasis on DKD, distinct mechanisms potential exogenous supplementation therapeutic strategy. Future research into could unravel novel treatment avenues for diseases.

Язык: Английский

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Imbalanced lipid homeostasis caused by membrane αKlotho deficiency contributes to the acute kidney injury to chronic kidney disease transition

Kidney International, Год журнала: 2023, Номер 104(5), С. 956 - 974

Опубликована: Сен. 5, 2023

After acute kidney injury (AKI), renal tubular epithelial cells (RTECs) are pathologically characterized by intracellular lipid droplet (LD) accumulation, which involved in RTEC and fibrosis. However, its pathogenesis remains incompletely understood. The protein, αKlotho, primarily expressed RTECs, is well known as an anti-aging hormone wielding versatile functions, membrane form predominantly acts a co-receptor for fibroblast growth factor 23. Here, we discovered connection between αKlotho LDs RTECs. Fluorescent fatty acid (FA) pulse-chase assays showed that deficiency seen homozygous mutated (kl/kl) mice or with ischemia-reperfusion (IRI)-induced AKI, inhibited FA mobilization from impairing adipose triglyceride lipase (ATGL)-mediated lipolysis lipophagy. This resulted LD accumulation underutilization. IRI-induced alterations were more striking deficiency. Mechanistically, promoted E3 ligase peroxin2 binding to ubiquitin-conjugating enzyme E2 D2, resulting ubiquitin-mediated degradation of ATGL common molecular basis Overexpression rescued preventing ubiquitination, thereby lessening fibrosis after AKI. suggests indispensable the maintenance homeostasis Thus, our study identified critical regulator turnover providing viable strategy AKI-to-chronic disease transition.

Язык: Английский

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P16INK4a deletion alleviates contrast-induced acute kidney injury by ameliorating renal cell apoptosis and suppressing inflammation and oxidative stress

Experimental Gerontology, Год журнала: 2024, Номер 187, С. 112372 - 112372

Опубликована: Фев. 1, 2024

Contrast-induced acute kidney injury (CI-AKI) is the third leading cause of hospital-acquired injury. Cellular senescence associated with CI-AKI. P16

Язык: Английский

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Associations between the TyG index and the ɑ-Klotho protein in middle-aged and older population relevant to diabetes mellitus in NHANES 2007–2016

Lipids in Health and Disease, Год журнала: 2024, Номер 23(1)

Опубликована: Июнь 21, 2024

Abstract Background The anti-aging protein Klotho has diverse functions in antioxidative stress and energy metabolism through several pathways. While it been reported that α-Klotho is downregulated patients with insulin resistance (IR), the association between IR complex controversial. triglyceride-glucose (TyG) index provided a practical method for assessing IR. With this mind, our study aimed to investigate relationship TyG soluble levels US populations, both without diabetes mellitus. Methods This cross-sectional analyzed data from middle-aged older participants National Health Nutrition Examination Survey (NHANES) conducted 2007 2016. were divided into two groups based on their mellitus status: those diabetes. To evaluate concentration of each group, series survey-weighted multivariable linear regression models employed. Furthermore, examine these variables, multivariable-adjusted restricted cubic spline curves subgroup analysis generated. Results involved 6,439 adults aged 40 years or older, mean age 57.8 ± 10.9 years. Among them, 1577 (24.5%) had A indicated presence significantly affected level. After considering all covariables, revealed decreased by 32.35 pg/ml (95% CI: -50.07, -14.64) one unit increase ( p < 0.001). decline elevated was more pronounced female population. In mellitus, non-linear observed. There no significant correlation observed when below 9.7. However, there an klotho 106.44 above 9.7 28.13, 184.74) = 0.008). Conclusion Our findings suggested may influence α-Klotho. seem be sex differences individuals Further studies are necessary validate findings.

Язык: Английский

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CUX1 attenuates the apoptosis of renal tubular epithelial cells induced by contrast media through activating the PI3K/AKT signaling pathway

BMC Nephrology, Год журнала: 2024, Номер 25(1)

Опубликована: Июнь 7, 2024

Abstract Objective Contrast media (CM) is a commonly applied drug in medical examination and surgery. However, contrast-induced acute kidney injury (CIAKI) poses severe threat to human life health. Notably, the CUT-like homeobox 1 (CUX1) gene shows protective effects variety of cells. Therefore, objective this study was provide new target for treatment CIAKI through exploring role possible molecular mechanism CUX1 CIAKI. Method Blood samples were collected from 20 patients with healthy volunteers. Human 2 (HK-2) cells incubated 200 mg/mL iohexol 6 h establish model HK-2 Subsequently, qRT-PCR used detect relative mRNA expression CUX1; CCK-8 flow cytometry assess proliferation apoptosis cells; levels IL(interleukin)-1β, tumor necrosis factor alpha (TNF-α) malondialdehyde (MDA) lactate dehydrogenase (LDH) activity cell culture supernatant detect; western blot observe PI3K/AKT signaling pathway related proteins [phosphorylated phosphoinositide 3-kinase (p-PI3K), PI3K, phosphorylated Akt (p-AKT), AKT]. Results significantly downregulated blood (CM; iohexol) reduced cells, promoted apoptosis, stimulated inflammation oxidative stress that caused damage. overexpression alleviated damage by improving level induced CM, inhibiting reducing LDH IL-1β, TNF-α MDA CM inhibited activity. Nevertheless, up-regulating could activate CM. Conclusion promotes proliferation, inhibits reduces CM-induced alleviate The may be correlated activation pathway.

Язык: Английский

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Fucoidan from Laminaria japonica protects renal tubular epithelial cells from uric acid induced NLRP3-mediated pyroptosis through inhibition of NF-κB pathway

Journal of Ethnopharmacology, Год журнала: 2024, Номер 335, С. 118614 - 118614

Опубликована: Июль 23, 2024

Язык: Английский

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Clemastine mitigates sepsis-induced acute kidney injury in rats; the role of α-Klotho/TLR-4/MYD-88/NF-κB/ Caspase-3/ p-P38 MAPK signaling pathways

Archives of Biochemistry and Biophysics, Год журнала: 2024, Номер 763, С. 110229 - 110229

Опубликована: Ноя. 26, 2024

Язык: Английский

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ACTIVATION OF KLOTHO/SIRT1 SIGNALING PATHWAY ATTENUATES MYOCARDIAL ISCHEMIA REPERFUSION INJURY IN DIABETIC RATS

Shock, Год журнала: 2024, Номер 62(3), С. 447 - 456

Опубликована: Июнь 21, 2024

ABSTRACT Diabetes and myocardial ischemia reperfusion (MIR) injury are characterized by oxidative stress, inflammation, autophagy disorders, cardiac contractile dysfunction. Klotho SIRT1 regulate the level of stress to participate in regulation many physiological functions such as cell survival, aging, apoptosis, autophagy, mitochondrial biogenesis, inflammation. We hypothesized that activation Klotho/SIRT1 signaling pathway could attenuate MIR diabetic rats. Type 1 diabetes model were established examine this hypothesis vivo . Primary rat cardiomyocytes H9c2 cells exposed high glucose conditions hypoxia/reoxygenation (H/R) insult vitro Hemodynamic parameters heart function, infarct size, markers or viability, mRNA protein expression measured. There was lower hearts than nondiabetic rats, well significantly increased levels decreased levels. Recombinant (rKlotho) agonist SRT1720 activating reduce restore These findings suggest plays an important role rKlotho have therapeutic potential for alleviating IR

Язык: Английский

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Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging

Опубликована: Авг. 5, 2024

The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia anomalies. Importantly, it associated with chronic pathologies (often age-related) that have inflammatory component. This includes atherosclerosis, diabetes Alzheimer’s disease. Its mode of action these diseases not well understood, but inhibits or regulates multiple major pathways. has a membrane form, soluble form (s-Klotho). Cytosolic postulated characterized. s-Klotho endocrine properties are incompletely elucidated. binds to FGF receptor 1c (FGFR1c) widely expressed (including endothelial cells). also attaches FGF23, FGF23/Klotho FGFRs. Thus, might be roaming FGF23 coreceptor, functions. Notably, (cell-bound soluble) counteracts inflammation, appears mitigate related aging (inflammaging). NF-κB NLRP3 inflammasome. inflammasome requires priming by NF-κB, produces active IL-1β, pores cell death (pyroptosis). In accord, countered inflammation injury induced toxins, damage-associated molecular patterns (DAMPs), cytokines, reactive oxygen species (ROS). blocks TGF-β Wnt ligands, which lessens fibrotic Low loss muscle mass (sarcopenia), as occurs diseases. counters inhibitory effects myostatin on muscle, reduces improves repair following injury. Inhibition factors may protective diabetic retinopathy age-related macular degeneration (AMD). review examines functions especially potential applications.

Язык: Английский

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