Soluble Klotho Research Articles

Soluble Klotho protects against glomerular injury through regulation of ER stress response

αKlotho (Klotho) has well established renoprotective effects; however, the molecular pathways mediating its glomerular protection remain incompletely understood. Recent studies have reported that Klotho is expressed in podocytes and protects glomeruli through auto- and paracrine effects. Here, we examined renal expression of Klotho in detail and explored its protective effects in podocyte-specific Klotho knockout mice, and by overexpressing human Klotho in podocytes and hepatocytes. We demonstrate that Klotho is not significantly expressed in podocytes, and transgenic mice with either a targeted deletion or overexpression of Klotho in podocytes lack a glomerular phenotype and have no altered susceptibility to glomerular injury. In contrast, mice with hepatocyte-specific overexpression of Klotho have high circulating levels of soluble Klotho, and when challenged with nephrotoxic serum have less albuminuria and less severe kidney injury compared to wildtype mice. RNA-seq analysis suggests an adaptive response to increased endoplasmic reticulum stress as a putative mechanism of action. To evaluate the clinical relevance of our findings, the results were validated in patients with diabetic nephropathy, and in precision cut kidney slices from human nephrectomies. Together, our data reveal that the glomeruloprotective effects of Klotho is mediated via endocrine actions, which increases its therapeutic potential for patients with glomerular diseases.

Composite Dietary Antioxidant Index and Plasma Levels of Soluble Klotho: Insights from NHANES.

The association between dietary antioxidants and soluble Klotho (S-Klotho) levels remains unknown. We investigated to explore whether the composite dietary antioxidant index (CDAI) was associated with serum levels of S-Klotho in the middle-aged population. Eligible participants were identified from the National Health and Nutrition Examination Surveys (NHANES) from 2007 until 2016. The CDAI was calculated from the intake of six dietary antioxidants. The serum levels of S-Klotho were measured via enzyme-linked immunosorbent assay (ELISA). Generalized linear and nonlinear models were established to analyze the relationship between CDAI and S-Klotho levels. Based on the S-Klotho quartiles, S-Klotho levels were higher in young women, Blacks, higher education, never smokers, lower waistlines, no medication use, and those with higher CDAI. Univariate analysis revealed that age, gender, race, smoking status, body mass index, waistline, and medication use were associated with serum levels of S-Klotho. When potential confounders were controlled, CDAI was significantly associated with S-Klotho levels. Subgroup analysis also revealed that this association remained significant in individuals who had the highest quartiles of CDAI, aged population (>60 years), male, and never smoker. A nonlinear relationship was observed between the CDAI and S-Klotho plasma concentrations. CDAI was positively correlated with plasma levels of S-Klotho after controlling for covariates. Further studies are needed to validate the current findings and explore the fundamental mechanisms.

Associations between the Healthy Eating Index-2015 and S-Klotho plasma levels: A cross-sectional analysis in middle-to-older aged adults.

The Healthy Eating Index (HEI) is a dietary index developed by the United States Department of Agriculture (USDA) to determine whether a diet adheres to US dietary guidelines. Soluble Klotho (S-Klotho) is a protein with essential anti-aging properties. However, whether HEI is linked to S-Klotho plasma levels is still debatable. This study aimed to assess the association between HEI-2015 and S-Klotho in middle-to-older aged adults in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2016. The study included 8456 middle-to-older aged (40-79 years old) participants. Multivariate regression models were used to estimate the correlation between HEI-2015 and S-Klotho concentrations. General additive models and two-piece-wise regression models were used to investigate the possible non-linear relationships between HEI-2015 and S-Klotho concentrations. Moreover, a stratified analysis of potential influencing factors was performed. A positive correlation was observed between HEI-2015 and S-Klotho plasma levels (β = 0.74, 95% CI: 0.21, 1.27, P = 0.0067). According to the two-piece-wise regression, the turning point of HEI-2015 was 45.15. When the range of HEI-2015 was from 0 to 45.15, the relationship between HEI and S-Klotho was insignificant (β = -0.87, 95% CI: -2.47, 0.73, P = 0.2858). However, when the range of HEI-2015 was from 45.15 to 100, HEI-2015 increased by 1 unit, the S-Klotho increased by 1.30 pg/ml (β = 1.30, 95% CI: 0.55, 2.05, P = 0.0007), suggesting a dose-response relationship. Furthermore, the stratified analysis showed that the association between HEI-2015 and S-Klotho concentrations was more significant in people with normal body mass index (P-interaction = 0.0161). There is a dose-response relationship between the HEI-2015 and S-Klotho in the middle-to-older aged adults. This relationship suggests that adherence to healthy dietary patterns may benefit the prevention of aging and health maintenance. The underlying mechanisms require further investigation.

PS-BPC11-4: LOW SOLUBLE KLOTHO IS ASSOCIATED WITH RESISTANT HYPERTENSION IN CKD: FROM THE KNOW-CKD STUDY

Objective: Apparent treatment-resistant hypertension (ATRH) is highly prevalent in chronic kidney disease (CKD) and is a risk factor for rapid progression of CKD. Soluble klotho is an extracellular domain of klotho released into the circulation. Although soluble klotho is known to be a risk factor for hypertension, the association between soluble klotho and ATRH is unknown. The aim of this study is to evaluate the association of soluble klotho with ATRH in CKD. Design and method: In this cross-sectional study, we analyzed 1,737 predialysis CKD patients enrolled in the prospective Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD). Apparent treatment-resistant hypertension was defined as systolic blood pressure > = 140 mm Hg or diastolic blood pressure > = 90 mm Hg with concurrent use of three antihypertensive medication classes or use of four or more antihypertensive medication classes regardless of blood pressure level. Serum klotho levels were measured using an enzyme-linked immunosorbent assay. Participants were divided into quartiles. Results: Among study subjects, 303 patients (17.4%) had ATRH. Prevalence of ATRH were 21.9%, 18.9%, 18.2% and 10.8% for the 1st to 4th quartiles of soluble klotho, respectively (p for trend < 0.001). The adjusted OR [95% CI] of 1st to 3th quartile of soluble klotho in reference to 4th quartile were 2.01 (1.32–3.06), 1.59 (1.04–2.42) and 1.69 (1.11–2.57). Conclusions: Soluble klotho level was inversely associated with the presence of ATRH in Korean predialysis CKD patients. This relationship was independent of various cardiovascular risk factors.

S-38-1: EPIGENETIC MECHANISM OF SALT-SENSITIVE HYPERTENSION

Nutritional and environmental factors contribute to the development of salt sensitive hypertension. DNA methylation, the most extensively studied epigenetic marker, may have more stable, longer lasting effects than transient changes in gene expression. Protein malnutrition during pregnancy causes prenatal programmed salt sensitive hypertension via aberrant DNA methylation of the angiotensin receptor, which is induced by exposure to excessive glucocorticoid in the fetal hypothalamus. In adults, salt sensitive hypertension induced by obesity is attributable to increased renal activity of Rac1 and mineralocorticoid receptor (MR) pathway, and adverse prenatal exposure induces transgenerational hypertension through activation of Rac1 and MR pathway by an epigenetic regulated mechanism. Finally, DNA methylation of Klotho in aged kidneys leads to a reduction in the circulating levels of soluble Klotho, and in turn, resulting in the activation of noncanonical Wnt5a and RhoA signaling in the vasculature and the development of aging associated salt sensitive hypertension. These findings indicate that epigenetic modulation has an important role in the development of salt sensitive hypertension throughout life.

Recent Advances in Hypertension: Epigenetic Mechanism Involved in Development of Salt-Sensitive Hypertension.

This review highlights recent insights into the epigenetic mechanism of salt-sensitive hypertension from the fetus to the elderly population, mainly focusing on the DNA methylation and histone modification-mediated regulation of hypertension-associated genes. Maternal malnutrition during pregnancy induces upregulation of AT1a (angiotensin receptor 1a) by aberrant DNA methylation, and increased AT1A activity in the hypothalamus develops prenatally programmed salt-sensitive hypertension through renal sympathetic overactivity. In addition, maternal lipopolysaccharide exposure during pregnancy induces upregulation of the Rac1 gene through histone modification by H3K9me2 across generations, resulting in salt-induced activation of the Rac1-MR (mineralocorticoid receptor) pathway in the kidney and the development of salt-sensitive hypertension in F4 and F5 offspring. In mice, aberrant DNA methylation of the Klotho gene, which regulates aging-associated hypertension, decreases the circulating soluble Klotho levels, leading to activation of the vascular Wnt5a-RhoA pathway and vasoconstriction and development of salt-sensitive hypertension because of decreased renal blood flow. A detailed understanding of the environmentally-induced epigenetic modulations related to salt-induced hypertension could be promising for developing preventive and therapeutic approaches to hypertension.

Serum biomarkers of colonic polyps in patients with acromegaly: a meta-analysis and systematic review.

In the past few decades, acromegaly and colonic polyps have been associated with an increased risk of colorectal cancer. Previous studies highlighted the importance of serum biomarkers of colonic polyps in patients with acromegaly. We reviewed studies on serum biomarkers of colonic polyps in patients with acromegaly, published on PubMed, Embase, Cochrane Library, Medline, and Chinese databases from January 1, 1966, to May 8, 2022. Meta-analysis and systematic review were conducted using Stata MP 14.0. Eight articles were included in this study. The mean (standard deviation) concentrations of serum biomarkers for acromegaly with and without colorectal polyps were extracted from these studies. Meta-analysis results showed that, compared to patients without colonic polyps, the levels of insulin-like growth factor-1 × upper limit of normal range (IGF-1 × ULN) and fasting insulin were significantly increased; while the levels of growth hormone (GH) were significantly decreased in patients with acromegaly and colonic polyps (IGF-1 × ULN: SMD 0.23; 95% CI 0.03-0.42, p < 0.05) (fasting insulin: SMD 0.95; 9 5% CI 0.11-1.8, p < 0.05) (GH: SMD - 0.25; 95% CI - 0.41 to - 0.08, p < 0.05). IGF-1 and FPG levels did not differ significantly (IGF-1: SMD -0.03; 95% CI - 0.22 to 0.17, p > 0.05) (FPG: SMD 0.14; 95% CI - 0.23 to 0.52, p > 0.05). The systematic review results suggest no significant differences in hemoglobin A1C, TSH, free thyroxine, FT4, T3, PRL, total cholesterol, HDL, LDL, fibrinogen, clathrate antigen, serum antigen 19-9, and α-fetoprotein levels, but serum Klotho levels. We present the first meta-analysis and systematic review of serum biomarkers in patients with acromegaly or colonic polyps. The prevalence of colonic lesion polyps, is associated with higher IGF-1 × ULN levels, higher insulin levels in acromegaly. Further research is required to confirm GH and serum soluble Klotho levels as biomarkers of colonic polyps. When IGF-1 × ULN, fasting insulin levels change in patients with acromegaly, the occurrence of colonic polyps should be monitored. Early detection may reduce the possibility of developing malignant colon neoplasms.

Renal Klotho safeguards platelet lifespan in advanced chronic kidney disease through restraining Bcl‐xL ubiquitination and degradation

BackgroundThrombosis and hemorrhage as two opposite pathologies are prevalent within the chronic kidney disease (CKD) population. Platelet homeostasis, which positions centrally in their pathogenesis, varies among the CKD population, while the underlying mechanism is poorly understood. ObjectiveTo investigate the change character and mechanism of platelet homeostasis in CKD and its association with renal Klotho deficiency. MethodsThe change character of platelet homeostasis and its association with renal Klotho deficiency were determined based on a cohort study as well as CKD mice and Klotho‐deficient mice with CKD. The effects on thrombopoiesis and platelet lifespan were examined by flow cytometry and platelet transfer. The underlying mechanism was explored by proteomics, flow cytometry, western blot, and immunoprecipitation. ResultsWe show that platelet count declines both in patient and mouse models with advanced CKD (Adv‐CKD) and is positively associated with circulating Klotho levels. Mechanistically, we identify that ubiquitin ligase UBE2O governs Bcl‐xL ubiquitination and degradation in platelets, whereas Adv‐CKD–induced oxidative stress in platelets stimulates p38MAPK to promote Bcl‐xL phosphorylation, which facilitates UBE2O binding to Bcl‐xL and subsequent Bcl‐xL degradation. Consequently, platelet lifespan is shortened in Adv‐CKD, culminating in platelet count decline. However, kidney‐secreted soluble Klotho protein restricts oxidative stress in platelets, thereby preserving Bcl‐xL expression and platelet lifespan. ConclusionsOur findings uncover the mechanism of platelet count decline in Adv‐CKD and identify renal Klotho as a long‐range regulator of platelet lifespan, which not only provide a molecular mechanism underlying CKD‐associated thrombocytopenia and hemorrhage but also offer a promising therapy choice.

Plasma S-Klotho level affects the risk of hyperuricemia in the middle-aged and elderly people

BackgroundSoluble Klotho (S-Klotho) is an anti-aging protein mainly secreted by the kidneys. Hyperuricemia is prevalent among middle-aged and elderly individuals, which affects the development of various chronic diseases. However, there are relatively few studies investigating the association between plasma S-Klotho levels and hyperuricemia in middle-aged and elderly individuals. This study sought to clarify the relationship between S-Klotho and the risk of hyperuricemia in middle-aged and elderly people.MethodsDuring 2007–2016, a total of 50,588 people participated in the National Health and Nutrition Examination Survey. Finally, 12,441 middle-aged and elderly people (aged 40–79) completed the soluble Klotho tests and had obtained complete data. S-Klotho was detected by ELISA kit, and the relationship between S-Klotho and hyperuricemia was assessed by multiple logistic regression. Hyperuricemia is defined as serum uric acid levels higher than or equal to 420 mmol/l in men and 360 mmol/l in women.ResultsIn the middle-aged and elderly, plasma S-Klotho levels were negatively correlated with hyperuricemia, and there was a saturation effect. The inflection point of S-Klotho was 927.8 pg/ml (logarithmic likelihood ratio test = 0.002). When plasma S-Klotho < 927.8 pg/ml, the prevalence of hyperuricemia in middle-aged and elderly individuals with higher levels of S-Klotho decreased by 25.6% compared with those with low levels of S-Klotho [Q4 vs Q1, OR: 0.744, 95%CI: (0.634, 0.874), P < 0.001]; In different age groups, S-Klotho had a significantly greater effect on hyperuricemia in middle-aged people [age: 40–65 years, Q4 vs Q1, OR (95%CI): 0.69 (0.58, 0.82), P < 0.001; Age > 65 years: Q4 vs Q1, OR (95%CI): 0.72 (0.56, 0.92), P = 0.008)].When the level of S-Klotho was higher, the risk of hyperuricemia in men was lower than that in women [male: Q4 vs Q1, OR (95%CI): 0.67 (0.56, 0.81), P < 0.001; female: Q4 vs Q1 (95%CI):0.72 (0.58, 0.88), P < 0.001].ConclusionsIn middle-aged and elderly individuals, plasma S-Klotho levels were inversely correlated with hyperuricemia, with a saturation effect. Given the limitations of the research results, the underlying mechanism between S-Klotho and hyperuricemia should be further explored.

Serum Phosphate Levels Modify the Impact of FGF23 Levels on Hemoglobin in Chronic Kidney Disease.

Anemia is a complication of chronic kidney disease (CKD). Phosphate and fibroblast growth factor-23 (FGF23) have a close relationship, as both are related to the pathogenesis of anemia. However, the possible interplay between them regarding their effect on anemia has not been evaluated. This was a cross-sectional study of 896 participants from the NEFRONA study (273 CKD3, 246 CKD4-5, 282 dialysis and 95 controls). The levels of 25(OH) and 1,25(OH)2 vitamin D, intact FGF23 (iFGF23) and soluble Klotho were measured, together with standard blood biochemistries. Anemia was defined as hemoglobin levels &lt; 13 g/dL in men and &lt;12 g/dL in women. Patients with anemia (407, 45.4%) were younger, mostly men and diabetic; were in advanced CKD stages; had lower calcium, 1,25(OH)2 vitamin D and albumin levels; and had higher ferritin, phosphate, intact PTH, and iFGF23. An inverse correlation was observed between hemoglobin and both iFGF23 and phosphate. The multivariate logistic regression analyses showed that the adjusted risk of anemia was independently associated with higher serum phosphate and LogiFGF23 levels (ORs (95% CIs) of 4.33 (2.11-8.90) and 8.75 (3.17-24.2), respectively (p &lt; 0.001)). A significant interaction between phosphate and iFGF23 (OR of 0.66 (0.53-0.83), p &lt; 0.001) showed that the rise in the adjusted predicted risk of anemia with the increase in iFGF23 was steeper when phosphate levels were low. Phosphate levels acted as modifiers of the effect of iFGF23 concentration on anemia. Thus, the effect of the increase in iFGF23 levels was stronger when phosphate levels were low.

Abstract 13265: Soluble Klotho Captures FGF23 to Mitigate Aortic Valve Inflammocalcification Associated With Chronic Kidney Disease

Calcific aortic valve disease (CAVD) is prevalent in the elderly people, particularly those with chronic kidney disease (CKD). Klotho (KL), an anti-aging protein, is expressed mainly in the kidney and the cardiovascular system as soluble and membrane forms. CKD patients have reduced levels of KL and increased levels of fibroblast growth factor 23 (FGF23), a pro-inflammatory mediator that may interact with soluble KL. We have reported that KL reduces the osteogenic response to high phosphate levels, a condition seen in CKD, in human aortic valve interstitial cells (AVICs). This study tested the hypothesis that soluble KL captures FGF23 to prevent aortic valve inflammocalcification induced by CKD. Methods and Results: We developed a novel CKD-CAVD model in old C57 mice (20 months) on AIN-76A diet and treated with adenine and calcitriol. Histology and immunostaining revealed tubular damage and monocyte/macrophage accumulation in kidney tissue of CKD mice. Aortic valve lesions, thickening and calcification, were evident in CKD mice. Serum FGF23 levels were increased while serum KL levels decreased. In addition, KL expression in the aortic valve was reduced. Recombinant FGF23 (0.04 mg/ml) elevated the inflammosteogenic activity in human AVICs. Treatment with recombinant KL (0.5 μg/ml) markedly decreased FGF23-induced inflammosteogenic activation in AVICs. Systemic analysis revealed that FGF23 upregulates YAP/SMAD3 signaling, and inhibition of YAP and SMAD3 reduced the effect of FGF23 on the inflammosteogenic activity in AVICs. In addition, recombinant KL suppressed the activation of this signaling mechanism in AVICs, and treatment of CKD mice with recombinant KL attenuated aortic valve lesions. However, denaturation of KL protein resulted in a loss of its effect on FGF23-induced AVIC inflammosteogenic activation. Further, incubation of FGF23 with recombinant KL not only resulted in the formation of complexes of these two proteins, but also markedly decreased the pro-inflammosteogenic effect of FGF23 in AVICs. Conclusion: This study demonstrates that CKD induces KL insufficiency and FGF23 accumulation that promote aortic valve lesions. Recombinant KL is capable of binding to FGF23 to suppress its pro-inflammosteogenic effect in the aortic valve.

Can sodium-glucose cotransporter 2 inhibitors ‘spin the thread of life’?

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were first used as antidiabetic agents that lower the blood glucose levels by promoting glycosuria. In recent years, randomised clinical trials have demonstrated that SGLT2i reduce cardiovascular-renal events and all-cause mortality in people with and without diabetes. The cardio-renal benefits observed are independent of glucose lowering effect and multiple mechanisms have been proposed for these results. SGLT2i can exert anti-ageing effects on the vasculature and other body organs through several signalling pathways including the activation of the nuclear factor erythroid-2-related factor 2 and the induction of antioxidant enzymes. We speculate that the pro-longevity effects of the SGLT2i are mediated by soluble Klotho, an anti-ageing kidney-derived hormone and an emerging therapeutic target for cardio-renal diseases.

Changes in bone biomarkers in response to different dosing regimens of cholecalciferol supplementation in children with chronic kidney disease.

The effect of different dosing regimens of cholecalciferol supplementation on bone biomarkers has not been studied in children with chronic kidney disease (CKD). This is a post hoc analysis of a multi-center randomized controlled trial which included children with CKD stages 2-4 with vitamin D deficiency (25-hydroxy vitamin D (25OHD) < 30ng/ml) randomized 1:1:1 to receive an equivalent dose of oral cholecalciferol as daily, weekly or monthly treatment. Markers of bone formation (bone alkaline phosphatase (BAP), procollagen I N terminal peptide (PINP)), bone resorption (tartarate-resistant acid phosphatase 5b (TRAP), C terminal telopeptide (CTX)), and osteocyte markers (intact fibroblast growth factor 23 (iFGF23), sclerostin) and soluble klotho were measured at baseline and after 3months of intensive replacement therapy. The change in biomarkers and ratio of markers of bone formation to resorption were compared between treatment arms. BAP and TRAP were expressed as age- and sex-specific z-scores. 25OHD levels increased with cholecalciferol supplementation, with 85% achieving normal levels. There was a significant increase in the BAP/TRAP ratio (p = 0.04), iFGF23 (p = 0.004), and klotho (p = 0.002) with cholecalciferol therapy, but this was comparable across all three therapy arms. The BAPz was significantly higher in the weekly arm (p = 0.01). The change in 25OHD (Δ25OHD) inversely correlated with ΔPTH (r = - 0.4, p < 0.001). Although cholecalciferol supplementation was associated with a significant increase in bone formation, the three dosing regimens of cholecalciferol supplementation have a comparable effect on the bone biomarker profile, suggesting that they can be used interchangeably to suit the patient's needs and optimize adherence to therapy. A higher resolution version of the Graphical abstract is available as Supplementary information.

A systematic review and meta-analysis demonstrating Klotho as an emerging exerkine

Klotho is an anti-aging protein with several therapeutic roles in the pathophysiology of different organs, such as the skeletal muscle and kidneys. Available evidence suggests that exercise increases Klotho levels, regardless of the condition or intervention, shedding some light on this anti-aging protein as an emergent and promising exerkine. Development of a systematic review and meta-analysis in order to verify the role of different exercise training protocols on the levels of circulating soluble Klotho (S-Klotho) protein. A systematic search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE through PubMed, EMBASE, CINAHL, CT.gov, and PEDro. Randomized and quasi-randomized controlled trials that investigated effects of exercise training on S-Klotho levels. We included 12 reports in the analysis, comprising 621 participants with age ranging from 30 to 65 years old. Klotho concentration increased significantly after chronic exercise training (minimum of 12 weeks) (Hedge’ g [95%CI] 1.3 [0.69–1.90]; P < 0.0001). Moreover, exercise training increases S-Klotho values regardless of the health condition of the individual or the exercise intervention, with the exception of combined aerobic + resistance training. Furthermore, protocol duration and volume seem to influence S-Klotho concentration, since the effect of the meta-analysis changes when subgrouping these variables. Altogether, circulating S-Klotho protein is altered after chronic exercise training and it might be considered an exerkine. However, this effect may be influenced by different training configurations, including protocol duration, volume, and intensity.

Klotho in Kidney Transplantation: A New and Important Target?

Klotho in Kidney Transplantation: A New and Important Target?

Association between serum klotho levels and cardiovascular disease risk factors in older adults

BackgroundKlotho deficiency is a significant predictor of cardiovascular disease (CVD)-related mortality and morbidity. However, research assessing the association between klotho and individual risk factors of CVD is limited. This study aimed to explore the association between circulating serum klotho levels and risk factors for CVD in adults.MethodsWe used the 2007–2016 National Health and Nutrition Examination Survey and included 13,154 participants for whom serum klotho levels were available. Body mass index (BMI), exercise, smoking status, alcohol consumption, hypertension, dyslipidemia, serum lipid parameters, and blood pressure were considered as CVD risk factors.ResultsCirculating klotho levels were negatively associated with being overweight (beta coefficient: − 22.609, p = 0.0025), obesity (beta coefficient: − 23.716, p = 0.0011), current smoking (beta coefficient: − 46.412, p < 0.0001), and alcohol consumption (beta coefficient: − 51.194, p < 0.0001). There was a positive association between serum klotho levels and no history of dyslipidemia (beta coefficient: 15.474, p = 0.0053). Serum klotho levels were significantly decreased by a unit increase in triglycerides (beta coefficient: − 0.117, p = 0.0006) and total cholesterol (beta coefficient: − 0.249, p = 0.0002). There was a significant non-linear relationship between serum klotho levels, triglycerides, and total cholesterol.ConclusionsLower serum klotho levels are associated with certain CVD risk factors, including high BMI, smoking, alcohol consumption, and lipid parameters (triglycerides and total cholesterol). This study suggests that the soluble klotho level may be a potential marker for CVD risk.

Angiotensin II receptor type 1 blockade regulates Klotho expression to induce TSC2-deficient cell death

Lymphangioleiomyomatosis (LAM) is a multisystem disease occurring in women of child-bearing age manifested by uncontrolled proliferation of smooth muscle-like "LAM" cells in the lungs. LAM cells bear loss-of-function mutations in tuberous sclerosis complex (TSC) genesTSC1and/orTSC2, causing hyperactivation of the proliferation promoting mammalian/mechanistic target of Rapamycin complex 1 pathway. Additionally, LAM-specific active renin-angiotensin system (RAS) has been identified in LAM nodules, suggesting this system potentially contributes to neoplastic properties of LAM cells; however, the role of this renin-angiotensin signaling is unclear. Here, we report that TSC2-deficient cells are sensitive to the blockade of angiotensin II receptor type 1 (Agtr1). We show that treatment of these cells with the AGTR1 inhibitor losartan or silencing of theAgtr1gene leads to increased cell deathinvitroand attenuates tumor progressioninvivo. Notably, we found the effect of Agtr1 blockade is specific to TSC2-deficient cells. Mechanistically, we demonstrate that cell death induced by Agtr1 inhibition is mediated by an increased expression of Klotho. In TSC2-deficient cells, we showed overexpression of Klotho or treatment with recombinant (soluble) Klotho mirrored the cytocidal effect of angiotensin blockade. Furthermore, Klotho treatment decreased the phosphorylation of AKT, potentially leading to this cytocidal effect. Conversely, silencing of Klotho rescued TSC2-deficient cells from cell death induced by Agtr1 inhibition. Therefore, we conclude that Agtr1 and Klotho are important for TSC2-deficient cell survival. These findings further illuminate the role of the RAS in LAM and the potential of targeting Agtr1 inhibition in TSC2-deficient cells.

The association between serum soluble Klotho and chronic kidney disease among us adults ages 40 to 79 years: Cross-sectional study.

BackgroundChronic kidney disease (CKD) is diagnosed in more than 26 million U.S. people, which increases the risk of many adverse events. α-Klotho was reported to have potential effects on kidney function. The purpose of this study was to investigated whether CKD prevalence is associated with α-Klotho levels in the U.S. people aged 40–79 years.MethodsThirteen thousand five hundred eighty-nine participates in the National Health and Nutrition Examination Survey 2007–2016 aged 40–79 with information of Klotho and kidney function were included. The association between CKD and Klotho was calculated using multivariate linear or logistic regression models with adjustment of several possibly confounding variables. Subgroup analyses stratified by age, BMI, and diabetes mellitus were conducted. The non-linear relationship between Klotho and dependent variables with a non-normality of residues was assessed using smooth curve fitting and the segmented regression (also known as piece-wise regression) models.ResultsAmong 13,589 participants, the median of Klotho levels was 803.10 pg/mL, mean eGFR of all participants was 86.96 (SD = 19.88) mL/min/1.73 m2, and CKD was diagnosed in 20.11% of them (N = 2733). In the fully adjusted model, eGFR was positively associated with Klotho (β = 5.14, 95%CI 4.13-6.15, p < 0.001), while CKD was negatively associated with Klotho (stage ≧ 1, OR = 0.62, 95% CI 0.50–0.76, p < 0.001; stage ≧ 3, OR = 0.31, 95% CI 0.24–0.41, p < 0.001). The non-linear relationship showed that occurrence of CKD stage> 1 and albuminuria were negatively associated with Klotho when Klotho smaller than turning point (for whether CKD stage> 1, turning point K = 6.85, Klotho < K, OR = 0.44, p < 0.001; for albuminuria, turning point K = 6.84, Klotho < K, OR = 0.59, p < 0.001).ConclusionSerum soluble Klotho levels were positively associated with eGFR and negatively associated with the prevalence of CKD, especially in elderly, obese, and diabetic patients.

Does Dapagliflozin influence arterial stiffness and levels of circulating anti-aging hormone soluble Klotho in people with type 2 diabetes and kidney disease? Results of a randomized parallel group clinical trial.

ObjectiveThe mechanisms that explain the cardio-renal benefits of sodium glucose co-transporter 2 (SGLT-2) inhibitors are unknown. The effect of SGLT-2 inhibitors on arterial aging, measured by Aortic Pulse Wave Velocity (Ao-PWV) and Soluble Klotho (s-Klotho), a circulating anti-aging biomarker of arterial health are also unclear.Design/SettingA 24-week single center randomized controlled trial (registry number/ EudraCT Number: 2013-004042-42) comparing Dapagliflozin and Ramipril (D+R) versus Ramipril (R) on the primary endpoint of urine albumin excretion rate (AER) and pre-specified secondary endpoints of Ao-PWV and biomarkers of arterial aging [s-Klotho and Fibroblast Growth Factor 23 (FGF-23)]. People with type 2 diabetes who had estimated glomerular filtration rate (eGFR) > 60 ml/min and residual microalbuminuria on maximum tolerated renin angiotensin system (RAS) inhibition were included in this study.ResultsIn total, 33 participants (male 73%) were randomized to either D+R (n = 17) or R (n = 16) arms. After 24 weeks of treatment, Ao-PWV (mean ± SD) did not change significantly from baseline D +R [9.06 ± 1.91 m/s to 9.13 ± 2.03 m/s], and R [9.88 ± 2.12 m/s to 10.0 ± 1.84 m/s]. AER fell significantly by 43.5% (95% CI: −57.36%, −29.56%; p < 0.01) in people in the D+ R arm only. We do not observe any significant changes in FGF-23 or s-Klotho. HbA1c and Angiotensin 1–7 fell significantly only in D + R arm.ConclusionsThe combination of Dapagliflozin and Ramipril had no effects on Ao-PWV and s-Klotho which are biomarkers of arterial aging and cardio-renal risk. Our data suggest that the early cardio-renal benefits observed with SGLT-2 inhibitors are unlikely to be related to an improvement in arterial aging.

Adherence to Mediterranean Diet and Soluble Klotho Level: The Value of Food Synergy in Aging.

Diets for healthy aging have long been an intriguing issue. The current study makes a head-to-head comparison of four dietary patterns and their associations with soluble Klotho (s-Klotho) levels, an aging-related marker. The dietary data of 7906 subjects were obtained from the National Health and Nutrition Examination Survey 2007–2016. Each participant was given a score or was grouped according to four dietary patterns, namely the Mediterranean adherence diet score (MDS), the low-carbohydrate-diet score, a low-fat diet, and a low-carbohydrate diet. Subsequently, the associations with s-Klotho were examined using linear regression analyses. In addition, we calculated the odds ratio (OR) for aging in different dietary patterns, taking the lowest quartile of s-Klotho as a reference for aging. The MDS was the only dietary pattern that revealed a relationship with s-Klotho levels. The positive association (β coefficient: 9.41, p < 0.001) remained significant when dividing the MDS into tertiles (Tertile 2: β coefficient: 36.87, p < 0.001; Tertile 3: β coefficient: 45.92, p < 0.001) and grouping participants into subsets by sex, age, and BMI. A lower OR for aging was observed in higher MDS groups (Tertile 2: OR = 0.86, p = 0.026; Tertile 3: OR = 0.77, p < 0.001). However, when analyzed separately, merely three out of nine components of the MDS, namely alcohol consumption (β coefficient: 42.54, p < 0.001), fruit (β coefficient: 11.59, p = 0.029), and dairy products (β coefficient: 8.55, p = 0.032), showed a significant association with s-Klotho. The Mediterranean diet adopts a food-based approach, which has the merit of valuing the complex interactions between foods and their constituents, and further brings benefits to healthy aging.