Search Results (63)

Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric renal failure, but the molecular mechanisms driving these conditions are not yet fully understood. Fibroblast Growth Factor 23 (FGF23) and its co-receptor α-KLOTHO play crucial roles in regulating calcium and phosphate homeostasis in adult kidneys, but their roles in kidney development and the pathogenesis of CAKUT remain unclear. Because of that, we analyzed the spatial and temporal expression of FGF23 and α-KLOTHO in normal fetal kidney development and CAKUT using an immunofluorescence technique. Our results demonstrate a dynamic pattern of FGF23 and α-KLOTHO expression in healthy kidney development, with FGF23 levels decreasing and α-KLOTHO levels increasing with gestational age. Also, we showed that FGF23 expression was significantly reduced in horseshoe (HKs) and duplex kidneys (DKs), while α-KLOTHO expression remained unchanged across all CAKUT conditions. Based on our results, we suggest that altered FGF23 expression in CAKUT contributes to disease pathogenesis and may represent a potential therapeutic target. Full article

Cellular senescence is a hallmark of aging and contributes to age-related diseases, including diabetic nephropathy (DN). Additionally, macrophage-mediated inflammation has been linked with DKD. Therefore, we investigated the effect of macrophage depletion on kidney cell senescence in DN, focusing on the relationship between the GDF-15 and Klotho signaling pathways. Wistar albino rats (n = 24) were divided into four groups: healthy control, liposomal clodronate (LC)-treated healthy, diabetic, and LC-treated diabetic groups. Rats in the LC-treated healthy, diabetic, and LC-treated diabetic groups were intravenously administered LC once a week for 4 weeks. Rat models of type 2 diabetes were successfully established via the administration of streptozotocin and a high-fat diet, as evidenced by increased blood glucose levels, kidney weight to body weight (KW/BW) ratio, serum albumin, creatinine, and urea levels, kidney damage, and oxidative stress. However, LC-mediated macrophage depletion reduced the KW/BW ratio, improved serum and oxidative parameters, decreased inflammatory markers (IL-6 and TNF-α), and ameliorated oxidative stress. Additionally, LC treatment promoted macrophage polarization towards the anti-inflammatory phenotype, downregulated GDF-15 expression, upregulated Klotho expression, and ameliorated kidney damage. In conclusion, macrophage depletion combats kidney senescence by modulating Klotho and GDF-15, indicating their potential as novel targets in DN treatment. Full article

α-Klotho is an anti-aging protein linked to various age-related diseases. Environmental metal exposure has been associated with oxidative stress and aging, but its effect on α-Klotho levels remains unclear. This study investigated the relationship between urinary metal concentrations and serum α-Klotho levels using data from the National Health and Nutrition Examination Survey (NHANES) 2007–2016 cycles. A total of 4071 adults aged 40 to 79 years were included in the analysis. After adjusting for potential confounders, positive associations were found between serum α-Klotho levels and barium (Ba), cesium (Cs), and molybdenum (Mo), while tungsten (W) and uranium (U) were negatively correlated with α-Klotho levels. The combined effects of multiple metals were further analyzed using the qgcomp model, which demonstrated a negative correlation between increased metal mixtures and serum α-Klotho levels. Specifically, U, total arsenic (t-As), W, cadmium (Cd), antimony (Sb), and lead (Pb) contributed to the reduction of α-Klotho levels, while Ba, Cs, dimethylarsinic acid (DMA), Mo, thallium (Tl), and cobalt (Co) were positively associated with α-Klotho levels. These findings suggest that exposure to certain metals, particularly in combination, may reduce serum α-Klotho levels, potentially accelerating aging processes. Further studies should investigate the underlying mechanisms responsible for these associations. Full article

The Klotho gene is recognized for its anti-aging properties. Its downregulation leads to aging-like phenotypes, whereas overexpression can extend lifespan. Klotho protein exists in three forms: α-klotho, β-klotho and γ-klotho. The α-klotho has two isoforms: a membrane-bound form, primarily in the kidney and brain, and a secreted klotho protein present in blood, urine, and cerebrospinal fluid. Klotho functions as a co-receptor for fibroblast growth factor-23 (FGF23), regulating phosphate metabolism. The membrane-bound form controls various ion channels and receptors, while the secreted form regulates endocrine FGFs, including FGF19 and FGF21. The interaction between β-klotho and FGF21 in muscle is critical in the development of sarcopenic obesity. This systematic review, registered in PROSPERO and conducted following PRISMA guidelines, evaluates klotho levels in individuals with obesity or sarcopenic obesity. The study includes overweight, obese, and sarcopenic obese adults compared to those with a normal body mass index. After reviewing 713 articles, 20 studies were selected, including observational, cross-sectional, cohort studies, and clinical trials. Significant associations between klotho levels and obesity, metabolic syndrome (MS), and cardiovascular risk were observed. Exercise and dietary interventions positively influenced klotho levels, which were linked to improved muscle strength and slower decline. Klotho is a potential biomarker for obesity, MS, and sarcopenic obesity. Further research is needed to explore its mechanisms and therapeutic potential. Full article

Background/Objectives: Soluble αKlotho (sαKlotho) and fibroblast growth factor 23 (FGF-23) are increased in acute heart failure (AHF). This study aimed to assess changes in serum sαKlotho and FGF-23 concentrations during an episode of AHF as well as the usefulness of both biomarkers for predicting long-term prognosis. Methods: The study included 104 consecutive patients hospitalized in t he intensive cardiac care unit due to AHF (mean age, 65.8 ± 14.6 years; mean ejection fraction, 31.4% ± 14). New-onset AHF was reported in 43.3% of the population. Blood samples were measured at entry and on discharge from hospital. The main clinical outcomes assessed in this study were all-cause mortality or rehospitalization due to HF during a 3-year follow-up. Results: At admission sαKlotho, FGF-23, and NT-pro BNP levels, compared with discharge, were significantly higher at p < 0.001, p < 0.001, and p < 0.001 respectively. The 3-year Kaplan–Meier analysis, based on tertiles, revealed, for sαKlotho levels from Tertile 1 on admission and at discharge, a 2-fold higher rate of all-cause mortality or rehospitalization for HF compared with Tertile 3 (p = 0.006 and p = 0.028, respectively). One-third of patients showed an increase in FGF-23 and sαKlotho levels during hospitalization. Patients with the highest percentage increase in the levels of both biomarkers had an elevated risk of all-cause morality or hospitalization for HF (hazard ratio, 2.75; confidence interval, 1.19–6.35; p = 0.02). Conclusions: sαKlotho and FGF-23 levels are elevated during an episode of AHF. Low sαKlotho levels are associated with an increased risk of all-cause mortality or rehospitalization for HF. Increases in sαKlotho and FGF-23 values during hospitalization identify patients with poor prognosis. Full article

Klotho, initially identified as an anti-aging gene, has been shown to play significant roles in cancer biology. Alongside α-Klotho, the β-Klotho and γ-Klotho isoforms have also been studied; these studies showed that Klotho functions as a potential tumor suppressor in many different cancers by inhibiting cancer cell proliferation, inducing apoptosis and modulating critical signaling pathways such as the Wnt/β-catenin and PI3K/Akt pathways. In cancers such as breast cancer, colorectal cancer, hepatocellular carcinoma, ovarian cancer, and renal cell carcinoma, reduced Klotho expression often correlates with a poor prognosis. In addition, Klotho’s role in enhancing chemotherapy sensitivity and its epigenetic regulation further underscores its potential as a target for cancer treatments. This review details Klotho’s multifaceted contributions to cancer suppression and its potential as a therapeutic target, enhancing the understanding of its significance in cancer treatment and prognoses. Full article

Background: Childhood obesity is a major public health concern, being linked to an increased risk of metabolic disorders and cardiovascular disease. Even in childhood, obesity is associated with systemic low-grade inflammation, which is a critical factor in the development of atherosclerosis and a predictor of cardiovascular morbidity and mortality. Objectives: To describe the prevalence of obesity and examine the relationship between IL-6, TNF-α, adiponectin, leptin, the leptin/adiponectin (L/A) ratio, and Klotho levels with BMI in children. Methods: This cross-sectional study included children aged 10–14 years from La Rioja, Spain. Participants were selected based on BMI criteria for overweight (85th–95th percentiles) and obesity (>95th percentile). Socio-demographic and anthropometric data and blood samples were collected and analyzed for IL-6, TNF-α, adiponectin, leptin, and Klotho. Results: A total of 340 participants were included, with 276 (81.2%) classified as normal weight and 64 (18.8%) as overweight or obese. Mean age was similar between groups (p = 0.40). Obesity was more prevalent in males (59.4%, p = 0.048). Obese participants had higher mean birth weight (p = 0.003), current height (p = 0.04), BMI (p < 0.0001), and abdominal circumference (p < 0.0001). BMI correlated positively with leptin (r = 0.54, p = 0.0008) and the L/A ratio (r = 0.40, p = 0.025), showing sex-specific differences. Conclusions: This study underscores leptin and the L/A ratio as potential biomarkers of metabolic dysregulation in childhood obesity, particularly in females. Longitudinal studies are needed to confirm these findings and assess the clinical utility of these biomarkers in pediatric obesity management. Full article

Gliomas are the most common and lethal forms of malignant brain tumors. We attempted to identify the role of the aging-suppressor Klotho gene and Klotho protein in the immunopathogenesis of gliomas. We examined Klotho genetic variants by PCR-RFLP and measured serum Klotho levels using the ELISA method. We found a statistically significantly increased frequency of rs1207568A allele and rs1207568 GA genotypes in co-dominant, dominant and over-dominant models in grade IV as compared to grade II and III glioma patients. The levels of soluble α Klotho (sαKL) were significantly lower in grade III and IV glioma patients than in healthy controls (p = 0.034; 0.0083). Patients with sαKL levels above 2500 pg/mL survived significantly longer than patients with sαKL below 2500 pg/mL (p = 0.038). We also found a positive correlation of the serum levels of sαKL with seven biomarkers, like angiogenic vascular endothelial growth factor (p = 0.0008), chemokine fractalkine (p = 0.0009), interferon γ (p = 0.003), glial derived neurotrophic factor (p = 0.0268), pro-inflammatory and pro-Th1 cytokine IL-6 (p = 0.0347), anti-inflammatory, pro-Th2 cytokines IL-4 (p = 0.0037) and IL-13 (p = 0.0004). Our results suggest the impact of Klotho genetic variants and Klotho levels on advanced-grade glioma. Full article

Phthalates are widely used chemicals with ubiquitous human exposure. Evidence indicated that phthalate exposure was associated with an increased risk of aging-related diseases. Klotho is a transmembrane protein with anti-aging functions, and its association with phthalates remains unknown. To find the association between phthalate exposure and serum α-Klotho, a cross-sectional study was performed in 4482 adults (40–79 years old) who completed the National Health and Nutrition Examination Survey (NHANES) (2007–2016). As shown in the results of multivariable linear regression analyses, mono(carboxynonyl) phthalate (MCNP) and mono-n-butyl phthalate (MBP) were inversely associated with α-Klotho, and the regression coefficients of MCNP and MBP were −1.14 (95% confidence interval (CI): −2.00, −0.27) and −0.08 (95% CI: −0.14, −0.02). Subgroup analyses based on the quartiles of each phthalate metabolite showed that both MCNP and MBP were only inversely associated with α-Klotho in the subgroups of the highest levels. For mono-isobutyl phthalate (MIBP), the inverse association with α-Klotho was only statistically significant in the subgroup of the lowest level, and the regression coefficient was −26.87 (95% CI: −52.53, −1.21). Our findings suggest that α-Klotho might be involved in the association of phthalate exposure with aging-related diseases. Future research investigating the causality between phthalates and α-Klotho and its underlying mechanisms is encouraged. Full article

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

Background/Objectives: The survival rate among pediatric cancer patients has reached 80%; however, these childhood cancer survivors (CCSs) are at a heightened risk of developing chronic conditions in adulthood, particularly kidney and cardiovascular diseases. The aims of this study were to assess the serum α-Klotho and FGF23 levels in CCSs and to determine their association with nephro- and cardiotoxicity. Methods: This study evaluated a cohort of 66 CCSs who remained in continuous remission, with a mean follow-up of 8.41 ± 3.76 years. Results: The results of this study revealed that CCSs exhibited significantly higher levels of soluble α-Klotho compared to healthy peers (1331.4 ± 735.5 pg/mL vs. 566.43 ± 157.7 pg/mL, p < 0.0001), while no significant difference was observed in their FGF23 levels. Within the participant cohort, eight individuals (12%) demonstrated a reduced estimated glomerular filtration rate (eGFR) below 90 mL/min/1.73 m². The relationship between treatment with abdominal radiotherapy and reduced eGFR was confirmed (p < 0.05). No correlations were found between potential treatment-related risk factors, such as chemotherapy or radiation therapy, serum levels of α-Klotho and FGF23, and nephro- and cardiotoxicity. Conclusions: In conclusion, this preliminary cross-sectional study revealed elevated levels of α-Klotho among childhood cancer survivors but did not establish a direct association with anticancer treatment. The significance of elevated α-Klotho protein levels among CCSs warrants further investigation. Full article

This article reviews the role of fibroblast growth factor 23 (FGF23) protein in phosphate metabolism, highlighting its regulation of vitamin D, parathyroid hormone, and bone metabolism. Although it was traditionally thought that phosphate–calcium homeostasis was controlled exclusively by parathyroid hormone (PTH) and calcitriol, pathophysiological studies revealed the influence of FGF23. This protein, expressed mainly in bone, inhibits the renal reabsorption of phosphate and calcitriol formation, mediated by the α-klotho co-receptor. In addition to its role in phosphate metabolism, FGF23 exhibits pleiotropic effects in non-renal systems such as the cardiovascular, immune, and metabolic systems, including the regulation of gene expression and cardiac fibrosis. Although it has been proposed as a biomarker and therapeutic target, the inhibition of FGF23 poses challenges due to its potential side effects. However, the approval of drugs such as burosumab represents a milestone in the treatment of FGF23-related diseases. Full article

Being involved in various physiological and pathophysiological mechanisms (ageing, kidney damage, cardiovascular diseases, etc.), Klotho is a parameter of increasing interest. Studies in veterinary medicine are still rare, but it is exciting to find out whether the findings obtained can be transferred to animals. The aim of this study was therefore to investigate Klotho in cats. This study addressed α-Klotho concentrations in the serum of two groups of cats: one diseased group affected by hypertrophic cardiomyopathy (n = 27) and one healthy control group (n = 35). α-Klotho concentrations in serum were measured using an ELISA. The results were evaluated in the context of several echocardiographic measurement parameters in the diseased group. No significant difference between α-Klotho concentrations in the two groups was found. A slight negative correlation was found between α-Klotho concentrations and the relation of left atrium/aorta (La/Ao) in the diseased group. Gaining initial information on α-Klotho in cats, it was not possible to draw definite conclusions concerning cardiomyopathies in this species. The assessment of Klotho should be considered in terms of its broad implications in disease processes, but it is also recommended to focus on specific disease features. Both approaches might be promising as possible applications of Klotho in veterinary medicine. Full article

Background: This study sought to assess the effect of statin therapy on myocardial inflammation in a White New Zealand rabbit model of atherogenesis. Methods: The mRNA expression levels of pro-inflammatory, pluripotency, and aging-related markers were quantified following a controlled feeding protocol and statin treatments. Results: Following high-cholesterol diet induction, we observed significant upregulation in the myocardial mRNA levels of MYD88, NF-κB, chemokines (CCL4, CCL20, and CCR2), IFN-γ, interleukins (IL-1β, IL-2, IL-4, IL-8, IL-10, and IL-18), and novel markers (klotho, KFL4, NANOG, and HIF1α). In contrast, HOXA5 expression was diminished following a hyperlipidemic diet. Both statin treatments significantly influenced the markers studied. Nevertheless, rosuvastatin administration resulted in a greater reduction in MYD88, NF-kB, chemokines (CCL4, CCL20, and CCR2), and interleukins IL-1β, IL-8, KLF4, NANOG, and HIF1α than fluvastatin. Fluvastatin, on the other hand, led to a stronger decrease in IL-4. Downregulation of IL-2 and IL-18 and upregulation of IFNβ and HOXA5 were comparable between the two statins. Notably, rosuvastatin had a stronger effect on the upregulation of klotho and IL-10. Conclusion: Overall, statin therapy significantly attenuated inflammatory, pluripotency, and klotho expression in myocardial tissue under atherogenic conditions. Our findings also highlight the differential efficacy of rosuvastatin over fluvastatin in curtailing proatherogenic inflammation, which could have profound implications for the clinical management of cardiovascular disease. Full article

Tissue engineering approaches aim to provide biocompatible scaffold supports that allow healing to progress often in healthy tissue. In diabetic foot ulcers (DFUs), hyperglycemia impedes ulcer regeneration, due to complications involving accumulations of cellular methylglyoxal (MG), a key component of oxidated stress and premature cellular aging which further limits repair. In this study, we aim to reduce MG using a collagen-chondroitin sulfate gene-activated scaffold (GAS) containing the glyoxalase-1 gene (GLO-1) to scavenge MG and anti-fibrotic β-klotho to restore stem cell activity in diabetic adipose-derived stem cells (dADSCs). dADSCs were cultured on dual GAS constructs for 21 days in high-glucose media in vitro. Our results show that dADSCs cultured on dual GAS significantly reduced MG accumulation (−84%; p < 0.05) compared to the gene-free controls. Similar reductions in profibrotic proteins α-smooth muscle actin (−65%) and fibronectin (−76%; p < 0.05) were identified in dual GAS groups. Similar findings were observed in the expression of pro-scarring structural proteins collagen I (−62%), collagen IV (−70%) and collagen VII (−86%). A non-significant decrease in the expression of basement membrane protein E-cadherin (−59%) was noted; however, the dual GAS showed a significant increase in the expression of laminin (+300%). We conclude that dual GAS-containing Glo-1 and β-klotho had a synergistic MG detoxification and anti-fibrotic role in dADSC’s. This may be beneficial to provide better wound healing in DFUs by controlling the diabetic environment and rejuvenating the diabetic stem cells towards improved wound healing. Full article