Serum Klotho Levels Research Articles

Association between testosterone and serum soluble α-klotho in U.S. males: a cross-sectional study

PurposeTestosterone plays a crucial role in males, and the deficiency of testosterone leads to multiple adverse health conditions. Klotho is a recently discovered protein encoded by antiaging gene klotho. Both the levels of testosterone and klotho change with aging, so the relationship between them is worth exploring. The purpose of this study was to investigate whether total testosterone is associated with serum klotho levels in U.S. males aged 40–79 years.MethodsIncluded in this study were 3750 male participants from the 2011 to 2016 National Health and Nutrition Examination Survey, aged 40–79 years with included information on klotho and sex hormones. The sex steroid hormone levels and klotho concentrations were assayed in laboratories using the recommended methods according to Nutrition Examination Survey guidelines. The association between sex hormones and klotho was calculated using multivariate linear regression models after adjustment for several possible confounding variables.ResultsAmong the 3750 participants, the total testosterone concentration was 399.048 ± 184.780 ng/dL, and the testosterone deficiency prevalence was 1160 (30.942%). The geometric mean of serum klotho levels was 791.000 pg/mL. In the adjusted models, klotho increased 0.165 pg/mL for every 1 ng/dL increase of total testosterone (p = 0.004). In addition, estradiol (β 2.232; 95% CI 0.588–3.876; p = 0.032) and sex hormone-binding globulin (β 2.013; 95% CI 1.173–2.583; p = 0.002) were also positively associated with klotho concentrations.ConclusionThis study reported a significant association between klotho and sex hormones in the U.S. male population. The levels of klotho in men increased with total testosterone, estradiol and sex hormone-binding globulin levels, which may have implications for future research and clinical practice.

Association between Dietary Inflammatory Index and serum Klotho concentration among adults in the United States

BackgroundKlotho is a hormone that emerges as an antiaging biomarker. However, the influence of the dietary pattern’s inflammatory potential on serum Klotho levels in human populations, especially in a general adult population, remains unknown. This study aimed to evaluate the relationship between the dietary inflammatory index (DII) and serum Klotho concentrations in individuals living in the United States. Methods From the 2007–2016 National Health and Nutrition Examination Survey database, data of participants who completed the full 24-h dietary history and underwent serum Klotho testing were analyzed. The association between DII and serum Klotho concentrations was estimated using multivariable linear regression models. We also conducted segmented regression model to examine the threshold effect of DII on serum Klotho concentrations.ResultsA total of 10,928 participants were included, with a median serum Klotho concentration of 805.20 pg/mL (IQR: 657.58 − 1001.12) and a median DII of 1.43 (IQR: − 0.16 − 2.82). Multivariable regression showed that participants with high DII scores were associated with low serum Klotho concentrations; when classifying DII into quartiles, after full adjustment, participants in DII quartiles 3 and 4 showed a decrease in Klotho levels (25.27 and 12.44 pg/ml, respectively) compared with those in the lowest quartile (quartile 1) (95% CI: − 41.80, − 8.73 and − 29.83, 4.95, respectively; P for trend = 0.036). The segmented regression showed that the turning point value of DII was − 1.82 (95% CI: − 2.32, − 0.80). A 1-unit increase in DII was significantly associated with lower Klotho levels by − 33.05 (95% CI: − 52.84, − 13.27; P = 0.001) when DII ranges from − 5.18 to − 1.82; however, the relationship was not significant when DII ranges from − 1.82 to 5.42 (P > 0.05). Furthermore, stratified analyses indicated that the observed associations between DII and serum Klotho concentration were stronger among those aged ≥ 56 years, those with normal weight, and those without chronic kidney disease (P for interaction = 0.003, 0.015, and 0.041, respectively).ConclusionsIn summary, we indicated that there was a dose–response relationship between DII and serum Klotho concentrations, suggesting that adhering to an anti-inflammatory diet has beneficial effects on aging and health by increasing the serum Klotho concentration.

Association of α-klotho and lead and cadmium: A cross-sectional study

Epigenetic aging is associated with harmful health effects such as oxidative stress from heavy metal exposure. We considered the relationship between genes and heavy metals in association with oxidative stress and then investigated the association between serum α- klotho and lead and cadmium exposure among adults in the United States from 2007 to 2016 participating in the National Health and Nutrition Examination Survey (NHANES). Samples included 9800 adults aged 40 to 79 years with measurements of serum α-klotho, lead and cadmium, and complete covariate data. Lead and cadmium levels were measured by inductively coupled plasma mass spectrometry and serum α-klotho levels were measured using enzyme-linked immunosorbent assay (ELISA). Multivariate linear regression analysis was used to estimate the association between serum α-klotho and blood lead, blood cadmium, and urinary cadmium. A percent increase in blood lead, blood cadmium, and urinary cadmium was associated with a statistically significant 4.0 % (p < 0.001), 2.0 %, (p = 0.003) and 1.0 % (p = 0.020) decrease in serum klotho. After adjustment, a percent increase in blood lead was associated with a statistically significant 4.0 % (p < 0.001) decrease in serum klotho; blood and urinary cadmium did not show any statistically significant associations after adjustment (β (95 % CI), p-value for blood cadmium: 0.00 (−0.02–0.01), p = 0.573; urinary cadmium: −0.01 (−0.03–0.01), p = 0.210). Mean serum klotho levels showed a statistically significant decreasing trend with increasing blood lead quartiles (unadjusted and all-adjusted geometric means and 95 % confidence intervals of serum klotho (in pg/mL) for Q1, Q2, Q3, and Q4: unadjusted: 827.49 (814.20–840.92), 811.92 (794.73–829.48), 791.48 (775.11–808.19), and 772.01 (754.23–790.29); adjusted: 830.64 (805.53–856.45), 816.07 (789.18–843.87), 800.71 (773.71–828.57), and 784.31 (757.94–811.59)). Blood lead and levels were negatively associated with serum α-klotho levels in a representative population of US adults. These results suggest that blood lead levels may be associated with the serum levels of a protein associated with cognition and aging. Further research is recommended to investigate the causality behind such relationship.

The association between metabolic syndrome and the anti-aging humoral factor klotho in middle-aged and older adults

Background and aimsThe goal of the present study was to determine the association between metabolic syndrome (MetS) and serum klotho levels (pg/ml) in middle-aged and older adults. Material and methodsThe National Health and Nutrition Examination Survey database from the cycles 2013–2014 and 2015–2016 were used to examine serum klotho levels in subjects with MetS and its components defined according to the 2009 Harmonizing Joint Scientific Statement. Sex-specific general linear models adjusted for potential confounders were assembled to compare mean log klotho levels between subjects with MetS and their healthy counterparts. ResultsOf 5069 participants aged 40–79 years, the prevalence of MetS was 44.8% in men and 45.1% in women. Overall, older adults, men, non-Hispanic whites, smokers, alcohol users, and subjects with decreased renal function were characteristics associated with lower klotho levels. Notably, serum klotho levels in women progressively decreased as the number of MetS components increased. Multivariate models demonstrated that women with MetS had significantly lower mean log klotho levels (6.65 vs. 6.70; P < .05) than those who did not. Likewise, abdominal obesity (6.5 vs. 6.68; P < .05) and elevated triglycerides levels (6.64 vs 6.68; P < .05) were the MetS components independently correlated with lower klotho levels. ConclusionsMetS in middle-aged and older adults was significantly and inversely associated with serum klotho levels. This association was particularly seen in women, and subjects with abdominal obesity or elevated triglycerides.

Urine-Derived Stem Cell-Secreted Klotho Plays a Crucial Role in the HK-2 Fibrosis Model by Inhibiting the TGF-β Signaling Pathway.

Renal fibrosis is an irreversible and progressive process that causes severe dysfunction in chronic kidney disease (CKD). The progression of CKD stages is highly associated with a gradual reduction in serum Klotho levels. We focused on Klotho protein as a key therapeutic factor against CKD. Urine-derived stem cells (UDSCs) have been identified as a novel stem cell source for kidney regeneration and CKD treatment because of their kidney tissue-specific origin. However, the relationship between UDSCs and Klotho in the kidneys is not yet known. In this study, we discovered that UDSCs were stem cells that expressed Klotho protein more strongly than other mesenchymal stem cells (MSCs). UDSCs also suppressed fibrosis by inhibiting transforming growth factor (TGF)-β in HK-2 human renal proximal tubule cells in an in vitro model. Klotho siRNA silencing reduced the TGF-inhibiting ability of UDSCs. Here, we suggest an alternative cell source that can overcome the limitations of MSCs through the synergetic effect of the origin specificity of UDSCs and the anti-fibrotic effect of Klotho.

Association between serum uric acid and α-klotho protein levels in the middle-aged population.

This study investigated the association between hyperuricemia and serum klotho protein levels in a representative sample of adults in the United States. We included 11,734 adults aged 40–80 years with available data of serum klotho, uric acid, covariates related to demographics, health behavior-related variables, and medical histories. Hyperuricemia was defined as a serum uric acid level of ≥7.0 mg/dL in men and ≥6.0 mg/dL in women. The geometric mean of serum klotho was 806.5 pg/mL (95% confidence interval: 801.7–811.4). The log-klotho level was negatively correlated with the uric acid level (r = −0.154; p < 0.0001). After adjustment for potential covariates, each one-unit increase in uric acid was significantly associated with a decrease in the log-klotho level (adjusted beta = −0.028; p < 0.0001). Compared with subjects without hyperuricemia, those with hyperuricemia had significantly lower serum klotho levels (adjusted beta = −0.062; p < 0.0001). We found a significant inverse association between serum uric acid and serum klotho levels in the general population, that is, an increase in serum uric acid levels was associated with a decrease in klotho levels. This finding suggests that loss of klotho may be due to the progression of hyperuricemia or, subsequently, gout.

Effects of acute aerobic exercise on cytokines, klotho, irisin, and vascular endothelial growth factor responses in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease that causes cartilage and bone damage as well as disability. AIMS : The aim of this study was to examine the effects of acute aerobic exercise on cytokines such as serum interleukin-6 (IL-6), interleukin-1β (IL-1β), Tumor Necrosis Factor-α (TNF-α) and irisin, vascular endothelial growth factor(VEGF) and klotho in RA patients. METHODS: Forty RA patient and 40 healthy volunteers of the same age participated in this study. All participants walked on the treadmill for 30 minutes at 60-80% of maximal heart rate. Blood samples were taken before and immediately after the exercise. Serum levels of IL-6, IL1β, TNF-α and irisin, VEGF and klotho were measured by enzyme-linked immunosorbent analysis. RESULTS: Baseline levels of inflammatory cytokines, irisin, VEGF and klotho were found to be higher in RA patients compared to the control group. In both groups, there was an increase in serum klotho levels after exercise compared to baseline (p<0.05), while a decrease in IL1β, TNF-α levels were observed. While serum VEGF level decreased in RA group, it increased in the control group(p<0.05). Irisin levels decreased in both groups. IL-6 level did not change in the control group, while it increased in RA group. A single exercise session had an acute anti-inflammatory effect in RA patients. It can be concluded that acute aerobic exercise can be beneficial for patients with RA through cytokine, irisin, klotho and VEGF levels, and also it can be safely implemented to the RA rehabilitation program for additional anti-inflammatory effects. Trial registration ClinicalTrials.gov: NCT04439682.

The relationship between polycyclic aromatic hydrocarbons exposure and serum klotho among adult population

BackgroundKlotho is an important factor involving aging process. Recently, polycyclic aromatic hydrocarbons (PAHs) exposure was reported to have adverse impact on DNA methylation associated with aging. The aim of the current study was to determine the relationship between serum klotho and PAHs exposure in an adult population.MethodsA total of 2597 participants obtained from NHANES 2015–2016 were included in this cross-sectional study. Serum klotho levels were analyzed by enzyme-linked immunosorbent assay (ELISA). PAHs exposure was estimated by urinary sample using liquid chromatography-tandem mass spectrometry. The relationship between serum klotho and exposure to PAHS was analyzed by a multivariable linear regression model.Results2-napthol and 3-fluorene were significantly associated with decreased klotho. After fully adjusting pertinent variables, PAH exposure was significantly associated with decreased klotho, particularly in men.ConclusionIn the present study we highlighted the significant association between PAHs exposure and serum klotho levels. The importance of environmental effect on aging process and age-related disorders should be paid more attention and clinical intervention is necessary.

Serum Klotho and pulse pressure; insight from NHANES

BackgroundLow levels of the Klotho protein are associated with accelerated tissue aging, including arterial stiffness, in patients with cardiovascular and renal diseases. However, this association has not been examined in a diverse cohort. We aimed to investigate the association between serum Klotho protein levels and pulse pressure, as an indicator of arterial stiffness, in a cohort representative of the US population. MethodsWe used the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. Association between pulse pressure and Klotho levels as a continuous variable and in quartiles were examined using survey weight-adjusted linear regression models. Multivariable models were adjusted for age, gender, race, BMI, hypertension, diabetes, smoking, alcohol use, total cholesterol, and estimated GFR. ResultsOf the 13,362 participants, 3954(29.6%) were > 65 years, 5792(43%) were Caucasian, and 6773(50.7%) had hypertension. Mean(SD) Klotho was 0.85(0.31) ng/mL and pulse pressure was 55.8(18.5) mmHg. In unadjusted and adjusted models, each ng/mL increase in Klotho was associated with a 3.88mmHg (95%CI = −5.19,−2.57; P < 0.001) and 1.63mmHg (95%CI = −3.01,−0.24; P = 0.02) decrease in pulse pressure, respectively. Similarly, participants in the highest quartile of Klotho had lower pulse pressure than those in the lowest quartile (−3.05mmHg; 95%CI = −4.05,−2.05; P < 0.001), and this difference remained significant in adjusted models (−1.10mmHg; 95%CI = −2.20,−0.01; P = 0.05). ConclusionIn this large diverse cohort, we found an inverse and independent association between serum Klotho levels and pulse pressure suggesting that Klotho is associated with arterial stiffness. The mechanisms underlying this association need further study.

Effect of combined aerobic and resistance exercise on serum Klotho secretion in healthy young men -a pilot study.

The impact of combined aerobic and resistance exercise on Klotho (KL) secretion is unclear. Twelve healthy young men completed two randomized experimental trials: 1) resistance exercise (RE) and 2) resistance exercise with prior aerobic exercise (AE + RE). Following baseline blood pressure assessment and blood collection, the subjects in the RE trial maintained a supine position for 45 min, while the subjects in the AE + RE trial performed 45 min of aerobic exercise. After 45 min of resting or aerobic exercise, all subjects performed resistance exercise. Following resistance exercise, the subjects rested in a supine position for 60 min. Blood pressure assessment and blood collection were repeated. Aerobic and resistance exercise significantly increased serum KL concentrations, respectively (P < 0.05), and no additive effect of aerobic exercise on KL secretion was observed immediately after resistance exercise in the AE + RE trial compared with the RE trial. However, serum KL levels at 30 and 60 min after resistance exercise were significantly higher in the AE + RE trial than in the RE trial. Serum ET-1 concentrations were significantly increased only in the RE trial. In conclusion, combined aerobic and resistance exercise could maintain higher levels of serum KL secretion after exercise compared with resistance exercise only.

Patients with Earlobe Crease May Associate with Lower Concentration of the Age-Suppressing Hormone Klotho

ObjectiveEarlobe crease (ELC) has been considered as a skin sign of atherosclerosis, and its pathophysiological mechanism is still unclear. Our study aims to test the hypothesis that ELC patients with lower serum levels of the age-suppressing hormone Klotho, which is not only associated with premature aging but also with endothelial dysfunction, may be associated with atherosclerosis.MethodsA total of 135 patients aged 40–68 years underwent coronary angiography. According to the presence or absence of coronary heart disease (CAD) and ELC, they were divided into three groups: CAD group and ELC group (ELC group, n = 45); no ELC group (non-ELC group, n = 45). There was no ELC or CAD in the control group (control group, n = 45). Serum Klotho concentration was obtained by enzyme-linked immunosorbent assay (ELISA).ResultsThe Klotho level in the ELC group was 365.6 ± 38.1 pg/mL, while the Klotho level in the non-ELC group was 568.8 ± 44.9 pg/mL. It is worth noting that the Klotho level of the ELC group was significantly lower than that of the non-ELC group (P < 0.001). The serum Klotho level of the control group was higher than that of the non-ELC group (593.3±45.3 vs 568.8±44.9 pg/mL, P = 0.702), but the difference was not statistically significant. Multiple logistic regression analysis showed that the Klotho level is a parameter that affects the appearance of ELC.ConclusionSerum Klotho levels were considerably lower in patients with ELC. We concluded that the perturbations of Klotho in patients might be associated with ELC and with CAD.

Impact of a single bout of resistance exercise on serum Klotho in healthy young men.

BackgroundIt has been shown that Klotho protects vascular endothelial function. Given that a single bout of resistance‐exercise‐induced hypertensive stimulus causes endothelial dysfunction, we postulated that acute resistance exercise would reduce serum Klotho levels. In this respect, the reduction in serum Klotho levels would be associated with the response of flow‐mediated dilation (FMD). Therefore, the purpose of this study was to investigate the impact of acute resistance exercise on the Klotho response in serum. In addition, we examined the relationship between the serum Klotho and FMD responses following acute resistance exercise.MethodsTwelve untrained men participated in this study (20.4 ± 0.3 years). Following baseline measurements (blood pressure, blood collection, FMD), subjects performed leg extensions, which consisted of 10 repetitions for five sets at 70% of one‐repetition maximum. After the exercise, measurement of blood pressure, blood collection, and FMD assessment were repeated for 60 min. We analyzed Klotho and endothelin‐1 (ET‐1) concentrations in blood serum.ResultsAs expected, the exercise significantly elevated blood pressure and led to decreased FMD (p < 0.05). However, Klotho concentrations were significantly increased following exercise (p < 0.05). No correlation was observed in Klotho and FMD responses following acute resistance exercise. However, there was a significant positive correlation between Klotho and ET‐1 in response to resistance exercise (p < 0.05).ConclusionIn conclusion, the present study reveals that serum Klotho significantly increased following a single bout of resistance exercise. However, the increase in Klotho may not associate with the acute reduction in endothelial function.

Klotho and SIRT1 changes from pre-diabetes to diabetes and pre-hypertension to hypertension

BackgroundHypertension and diabetes are among the most important risk factors of cardiovascular diseases. Klotho and SIRT1 are known as anti-aging factors with beneficial effects on cardiovascular system. In this study we investigated the serum Klotho and SIRT1 levels in pre-diabetic and pre-hypertensive individuals and then in diabetic and hypertensive patients to see their relationship with these diseases.Method229 individuals divided into six groups with similar gender and age distribution 1—Control (normal BP and FBS) 2—pre-diabetic (FBS between 100 and 125 mg/dl) 3—diabetic (FBS ≥ 126 mg/dl), 4—pre-hypertensive (SBP 120–139 or DBP 80–89 mm Hg) 5—hypertensive (SBP ≥ 140 or DBP ≥ 90 mm Hg), and 6—patients with combined hypertension/diabetes. Serum levels of Klotho and SIRT1 were measured by ELISA method.ResultsSerum Klotho and STRT1 levels decreased in pre-diabetes and returned to normal in diabetic patients. Their concentration increased in pre-hypertension and recovered to normal in hypertension. In the physiologic range of FBS there is a negative correlation between Klotho and SIRT1 with FBS. When pathologic ranges of FBS added to analysis, the negative correlation abolished/U shaped. Also an inverse U shape correlation observed between Klotho and SIRT1 with MAP in the range of normal to hypertensive BP levels. There was an overall positive relationship between the serum levels of Klotho and SIRT1 themselves.ConclusionThe serum levels of the anti-aging proteins Klotho and SIRT1 increases or reduces at the onset of the disease, as a compensatory mechanism, but as the disease progresses their level recovers.

Low Serum Klotho Associated With All-cause Mortality Among a Nationally Representative Sample of American Adults.

α-Klotho (klotho) is a protein involved in suppressing oxidative stress and inflammation. In animal models, it is reported to underlie numerous aging phenotypes and longevity. Among a nationally representative sample of adults aged 40-79 years in the United States, we investigated whether circulating concentrations of klotho is a marker of mortality risk. Serum klotho was measured by ELISA on 10 069 individuals enrolled in the National Health and Nutrition Examination Survey between 2007 and 2014. Mortality follow-up data based on the National Death Index were available through December 31, 2015. After a mean follow-up of 58 months (range: 1-108), 616 incident deaths occurred. Using survey-weighted Cox regression models adjusted for age, sex, and survey cycle, low serum klotho concentration (<666 pg/mL) was associated with a 31% higher risk of death (compared to klotho concentration > 985 pg/mL, hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.00, 1.71, p = .05). Associations were consistent for mortality caused by heart disease or cancer. Associations of klotho with all-cause mortality did not appear to differ by most participant characteristics. However, we observed effect modification by physical activity, such that low levels of serum klotho were more strongly associated with mortality among individuals who did not meet recommendation-based physical activity guidelines. Our findings suggest that, among the general population of American adults, circulating levels of klotho may serve as a marker of mortality risk.

Soluble Klotho and Incident Hypertension.

Hypertension is associated with significant morbidity and mortality despite effective antihypertensive therapies. Soluble klotho is a circulating protein that in preclinical studies is protective against the development of hypertension. There are limited studies of klotho and blood pressure in humans. Within the Health, Aging, and Body Composition Study, a cohort of well-functioning older adults, soluble klotho was measured in serum. We evaluated the cross-sectional and longitudinal association between klotho and blood pressure, prevalent hypertension, incident hypertension, and BP trajectories. Analyses were adjusted for demographics, cardiovascular disease and kidney disease risk factors, and measures of mineral metabolism including calcium, phosphate, parathyroid hormone, 25(OH) vitamin D, and fibroblast growth factor 23. The median klotho concentration was 630 pg/ml (478-816, 25th to 75th percentile). Within the cohort, 2093 (76%) of 2774 participants had prevalent hypertension and 476 (70%) of the remaining 681 developed incident hypertension. There was no association between klotho and prevalent hypertension or baseline systolic BP, but higher klotho was associated with higher baseline diastolic BP (fully adjusted β=0.92 mmHg, 95% confidence interval, 0.24 to 1.60 mmHg, higher per two-fold higher klotho). Higher baseline serum klotho levels were significantly associated with a lower rate of incident hypertension (fully adjusted hazard ratio, 0.80; 95% confidence interval, 0.69 to 0.93 for every two-fold higher klotho). Higher klotho was also associated with lower subsequent systolic BP and diastolic BP (-0.16, 95% confidence interval, -0.31 to -0.01, mmHg lower systolic BP per year and -0.10, 95% confidence interval, -0.18 to -0.02, mmHg lower diastolic BP per year, for each two-fold higher klotho). Higher klotho is associated with higher baseline diastolic but not systolic BP, a lower risk of incident hypertension, and lower BP trajectories during follow-up.

Protective effect of soluble Klotho in pediatric patients undergoing cardiac surgery with cardiopulmonary bypass support-A pilot study.

The Klotho protein family plays important roles in several metabolic pathways. Soluble Klotho has been recently put forward as an antiaging protein, demonstrating renal and cardiovascular protective traits. Cardiopulmonary bypass (CPB) support during cardiac surgery has been implicated in several adverse outcomes in pediatric and adult patients. Our goal was to assess whether serum Klotho levels can be used to predict outcomes in children undergoing cardiac surgery with CPB due to congenital heart defects (CHDs). This prospective study was conducted on pediatric patients admitted to two Pediatric Cardiac Intensive Care Units, between 2012 and 2018. All patients were born with CHD and underwent corrective surgery with CPB. Sequential blood samples were analyzed by enzyme-linked immunosorbent assay for soluble Klotho levels at baseline, 2, 6, and 24 h after surgery. The association between Klotho levels and several demographic, intraoperative, and postoperative clinical and laboratory parameters was studied. Twenty-nine children undergoing cardiac surgery with CPB support were included. Serum Klotho levels were shown to significantly decrease 2 h after surgery and increase to baseline levels after 6 h (p < .001 and p < .05, respectively). Patients with low Klotho levels 2 h after surgery were at a 32-fold higher risk for developing postoperative complications (p = .015, odds ratio < 0.03). Moreover, Klotho levels at each of the four time points were lower in patients who developed postoperative complications. Cardiac surgery with CPB results in a significant decrease of serum Klotho levels 2 h after surgery in pediatric patients with CHDs, which can be used to predict development of postoperative complications in this patient population.

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration.

Hyperglycemic conditions (HG), at early stages of diabetic nephropathy (DN), cause a decrease in podocyte numbers and an aberration of their function as key cells for glomerular plasma filtration. Klotho protein was shown to overcome some negative effects of hyperglycemia. Klotho is also a coreceptor for fibroblast growth factor receptors (FGFRs), the signaling of which, together with a proper rate of glycolysis in podocytes, is needed for a proper function of the glomerular filtration barrier. Therefore, we measured levels of Klotho in renal tissue, serum, and urine shortly after DN induction. We investigated whether it influences levels of FGFRs, rates of glycolysis in podocytes, and albumin permeability. During hyperglycemia, the level of membrane-bound Klotho in renal tissue decreased, with an increase in the shedding of soluble Klotho, its higher presence in serum, and lower urinary excretion. The addition of Klotho increased FGFR levels, especially FGFR1/FGFR2, after their HG-induced decrease. Klotho also increased levels of glycolytic parameters of podocytes, and decreased podocytic and glomerular albumin permeability in HG. Thus, we found that the decrease in the urinary excretion of Klotho might be an early biomarker of DN and that Klotho administration may have several beneficial effects on renal function in DN.

The Effect of Six Weeks of Moderate-Intensity Endurance Training on Serum Levels of Klotho and Expression of the Fibroblast-23 Growth Factor Gene (FGF23) in the Hearts of Diabetic Rats: An Experimental Study

The Effect of Six Weeks of Moderate-Intensity Endurance Training on Serum Levels of Klotho and Expression of the Fibroblast-23 Growth Factor Gene (FGF23) in the Hearts of Diabetic Rats: An Experimental Study

MO440KLOTHO AS A BIOMARKER OF SUBCLINICAL CARDIOVASCULAR DISEASE IN CHRONIC KIDNEY DISEASE: A PROOF-OF-CONCEPT STUDY*

Abstract Background and Aims Cardiovascular disease (CVD) is the major cause of mortality among chronic kidney disease (CKD) patients. Reductions in serum Klotho levels are related to the prevalence of CVD in CKD patients. However, it is unclear whether circulating Klotho, and its expression in peripheral blood cells (PBCs), are associated with subclinical atherosclerotic cardiovascular disease (sCVD) in these subjects. In this proof-of-concept study, we analyzed in a group of CKD patients the relationship between Klotho and two markers of sCVD: ankle-brachial index (ABI) and carotid intima-media thickness (CIMT). Method Gene expression in PBCs and serum levels of Klotho and inflammatory cytokines (TNF, IL6 and IL10) were measured in 103 CKD patients (stages 3-4), older than 18 years of age, and without known atherosclerotic cardiovascular disease. Biochemical data were obtained following standardized clinical methods. The presence of sCVD was defined as ABI &amp;lt; 0.9 and/or CIMT ≥ 0.9 mm. Patients with ABI values ≥ 1.3 were excluded. Results Patients with sCVD presented lower serum and PBCs expression levels of Klotho (P&amp;lt;0.001 for both). Stratified analysis showed that upper tertiles of both serum and PBCs expression levels of Klotho presented significantly higher ABI (P&amp;lt;0.001 for both Klotho determinations) and lower CIMT (P&amp;lt;0.001 for serum levels and P&amp;lt;0.01 for KL expression in PBCs), which resulted in a lower prevalence of sCVD (P&amp;lt;0.001 for both determinations of Klotho). Correlation analysis showed that both serum and PBCs mRNA Klotho levels were positively correlated with ABI (r=0.556, P&amp;lt;0.0001; and r=0.373, P&amp;lt;0.0001, respectively) and inversely correlated with CIMT (r=-0.541, P&amp;lt;0.0001; and r=-0.437, P&amp;lt;0.0001, respectively). Among inflammatory markers, only serum IL6 levels presented significant associations with sCVD, being inversely related with ABI (r=-0.568, P&amp;lt;0.0001) and positively associated with CIMT (r=0.558, P&amp;lt;0.0001). Multiple regression analysis with ABI and CIMT as dependent variables demonstrated that both Klotho variables, together with serum IL6, were positively and significantly associated with ABI (adjusted R2=0.511, P&amp;lt;0,0001) and CIMT (adjusted R2=0.445, P&amp;lt;0,0001) values, independently of traditional and emergent cardiovascular risk factors. Multivariate logistic regression, using the presence/absence of sCVD as the dependent variable, showed that circulating Klotho, and its expression in PBCs constituted independent protective factors for sCVD [OR (95% CI): 0.993 (P=0.002) and 0.231 (P=0.025), respectively]. Receiver operating curve (ROC) analysis pointed to the prognostic ability for sCVD of serum Klotho (area under the curve [AUC]: 0.817, 95% CI: 0.736–0.898, P&amp;lt;0.001) and its gene expression in PBCs (AUC: 0.742, 95% CI: 0.647–0.836, P&amp;lt;0.001). Conclusion The reductions in serum soluble and PBCs expression levels of Klotho in CKD patients are independently associated with the presence of sCVD. Further research exploring whether therapeutic approaches to maintain or elevate the Klotho level could reduce the impact of CVD in CKD patients is warranted.

Comparison of serum human Klotho levels and thiol/disulfide homeostasis in women with polycystic ovary syndrome and in healthy women

ObjectivesWomen with polycystic ovary syndrome (PCOS) have an increased cardiometabolic risk. Similarly, it was previously shown that atherosclerotic and cardiovascular risk is increased in the general population with lower serum Klotho levels. The aim of this study was to investigate the lotho and thiol/disulfide levels in women with non-obese PCOS compared to healthy controls and also to investigate the relationship of serum Klotho and thiol/disulfide homeostasis with cardiometabolic risk factors. Materials and methodsIn this prospective case control study, human serum alpha Klotho levels and thiol/disulfide homeostasis of women with PCOS aged between 19-33 were compared to their age and BMI matched non – PCOS healthy controls. In addition, the correlation of these molecules with other metabolic markers/measurements were also investigated. ResultsMetabolic parameters such as mean waist circumference, lipid accumulation product, visceral adiposity index, fasting insulin, homeostasis model assessment of insulin resistance and triglyceride values were higher in the PCOS group (p = 0.038, p = 0.008, p = 0.001, p = 0.001, p = 0.002 and p = 0.002, respectively) compared to controls. However, mean serum Klotho and native thiol levels (respectively p < 0.0001 and p = 0.038) were lower compared to controls. Correlation analysis revealed that serum Klotho levels were negatively correlated with BMI, waist circumference, disulphide/total thiol, disulphide/native thiol, HOMA-IR and LAP-index. ConclusionsFindings of decreased serum Klotho and native thiol values of the PCOS group compared to controls and the negative correlation of serum Klotho levels with metabolic markers supports the idea that decreased Klotho may be another mechanism by which cardiovascular risk is increased in women with PCOS.